@article {pmid42784125,
year = {2026},
author = {Demir, ÜF and Karakuş Dilbaz, F},
title = {Anti-Amyloid Monoclonal Antibodies in Early Alzheimer Disease: Lecanemab and Donanemab.},
journal = {Neurology international},
volume = {18},
number = {9},
pages = {},
doi = {10.3390/neurolint18090171},
pmid = {42784125},
issn = {2035-8385},
abstract = {BACKGROUND/OBJECTIVES: Alzheimer disease (AD) causes progressive cognitive and functional loss and substantial caregiver and healthcare burden. Anti-amyloid monoclonal antibodies represent a shift toward biology-directed treatment in biomarker-confirmed early symptomatic AD, but modest clinical effects must be balanced against amyloid-related imaging abnormalities (ARIA), intensive monitoring, and implementation burden. Heterogeneity in trial populations, endpoints, dosing, stopping rules, and follow-up complicates interpretation. This narrative review critically integrates efficacy, safety, durability, biomarker, and implementation evidence for lecanemab and donanemab while preserving study-family relationships and avoiding unsupported cross-trial superiority claims.

METHODS: For this revised narrative review, a targeted PubMed/MEDLINE search covering the period from database inception was initially conducted before manuscript submission and was subsequently updated through 21 August 2026, supplemented by reference-list and citation tracking. Search terms combined Alzheimer disease with lecanemab, donanemab, anti-amyloid monoclonal antibody, ARIA, APOE, amyloid PET, open-label extension, real-world, clinical meaningfulness, implementation, and access. Sixty-two sources were purposively selected for a comprehensive narrative synthesis; no meta-analysis or formal certainty grading was performed.

RESULTS: Pivotal trials demonstrated statistically significant but modest average slowing of decline: Clarity AD showed a 0.45-point between-group difference in CDR-SB worsening at 18 months, and TRAILBLAZER-ALZ 2 showed a 3.25-point iADRS difference in the low/medium-tau population at 76 weeks. ARIA-E occurred in 12.6% of lecanemab-treated and 24.0% of donanemab-treated participants in the pivotal trials, with higher risk in APOE ε4 carriers. Extensions and biomarker analyses suggest persistent biological effects but are less secure for causal inference, and real-world evidence is currently more mature for lecanemab.

CONCLUSIONS: Both antibodies substantially reduce amyloid and modestly slow average clinical decline in selected patients, but neither restores lost function, greater amyloid clearance does not establish greater individual benefit, and cross-trial superiority cannot be inferred. Treatment requires biomarker-guided selection, APOE-informed risk counseling, serial MRI, infusion and ARIA-management capacity, and shared decision-making that incorporates cost, access, and patient/caregiver burden.},
}

@article {pmid42784228,
year = {2026},
author = {Zingler, G and Herdegen, T},
title = {In Patients Experiencing Pain and Inflammation, the Use of Non-Steroidal Anti-Inflammatory Drugs Is More Likely a Marker of the Observed Cardiovascular Risk Rather than Its Cause: A Viewpoint.},
journal = {Pharmacy (Basel, Switzerland)},
volume = {14},
number = {6},
pages = {},
doi = {10.3390/pharmacy14060139},
pmid = {42784228},
issn = {2226-4787},
abstract = {Non-steroidal anti-inflammatory drugs (NSAIDs) have been among the most frequently prescribed medications worldwide for several decades. Ongoing vigilance regarding their potential adverse effects on the gastrointestinal tract and kidneys remains critical. Over the past twenty years, accumulating evidence has indicated an increased cardiovascular (CV) risk associated with NSAID use, posing a significant challenge for both patients and healthcare providers. This issue has prompted the US Food and Drug Administration (FDA) to issue explicit warnings concerning NSAID use. Recent data and comparative analyses of existing publications provide a basis for critically re-evaluating the association between NSAID use and potential CV risk, particularly when NSAIDs are administered for approved indications such as the treatment of pain and inflammation in patients with arthritis. The debate regarding the CV safety of NSAIDs centers on establishing causality. It is necessary to determine whether NSAIDs directly induce CV risks by initiating new pathological processes or act as modulators that influence the severity of pre-existing susceptibilities. The evidence presented in this review supports the view that NSAIDs do not create new CV risks but reduce CV incidents in patients with inflammatory pathologies such as arthritis. Conversely, NSAIDs have been observed to slightly increase CV risk when used at inappropriate high doses or in patients without inflammatory pain, such as those with Alzheimer's disease or other vulnerable populations. This perspective shifts the focus from causality to context-based risk management. The distinction between risk generation and risk modulation is proposed as a framework for the rational use of NSAIDs. The potential for NSAIDs to exacerbate pre-existing CV risk is dependent on the context of morbidity, and is low when used for anti-inflammatory indications in populations with the highest benefit, i.e., those with inflammatory morbidities. A general condemnation of NSAIDs keeps relevant patient populations from the only anti-inflammatory analgetic pharmacotherapy so far available.},
}

@article {pmid42784819,
year = {2026},
author = {Barak, Y and Cheer, SM and Mullen, R},
title = {Oil on the brain: dementia in the popular press prior to the 1906 Alzheimer case report.},
journal = {The New Zealand medical journal},
volume = {139},
number = {1642},
pages = {15-20},
doi = {10.26635/6965.7443},
pmid = {42784819},
issn = {1175-8716},
mesh = {Humans ; New Zealand ; History, 19th Century ; *Newspapers as Topic/history ; *Dementia/history/etiology ; History, 20th Century ; *Alzheimer Disease/history ; },
abstract = {BACKGROUND AND AIMS: Concepts of dementia precede the description published by Alzheimer. Historically, the term was misunderstood and misused by the published newspapers of the nineteenth century. We aimed to describe the historical use of the term dementia in New Zealand newspapers.

METHOD: Papers Past is a project of the National Library of New Zealand that aims to digitise all New Zealand newspapers from 1839 onwards. There are 96,022,840 newspaper articles in this dataset.

RESULTS: There were 1,521 newspaper articles between 1839 and 1906 in which the word dementia appeared in the content or title. Of these, 165 met the inclusion criteria. Of included articles, 87 had a description of the condition, 92 mentioned a cause of dementia and 25 included a description of management. Categories were not mutually exclusive. The common cause of dementia described was mental impairment (N=44), with special emphasis on mania, postpartum depression and intellectual disability. This was followed by environmental factors (N=34) and alcohol use (N=26). The common form of management for dementia was incarceration within an asylum or a gaol, occurring in 18 of 25 reported cases. Specific treatments for dementia included: a blister to the neck, rheumatic balsam, milk with lime water, marine serum and cranial surgery.

CONCLUSION: The descriptions of dementia from newspaper articles were consistent with nineteenth century Western concepts of the disease, and the causes and treatment of dementia reflected the New Zealand environment and Pākehā culture during colonial times.},
}

Humans
New Zealand
History, 19th Century
*Newspapers as Topic/history
*Dementia/history/etiology
History, 20th Century
*Alzheimer Disease/history

@article {pmid42785112,
year = {2026},
author = {Cummings, JL and Scheltens, P},
title = {Evoke (+) trials of semaglutide for early alzheimer's disease: Innovations, lessons, and implications.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100677},
doi = {10.1016/j.tjpad.2026.100677},
pmid = {42785112},
issn = {2426-0266},
abstract = {The evoke and evoke+ trials for the treatment of early Alzheimer's disease (AD) with semaglutide were founded on the observation that semaglutide reduced the incidence of dementia in patients with type 2 diabetes. Non-clinical investigations support an effect of semaglutide on AD pathology. The evoke and evoke+ trials were large, well conducted, and innovative. These trials were negative, showing no clinical benefit of treatment with 14 milligrams of semaglutide for two years. Semaglutide produced a statistically significant and robust reduction in high sensitivity C-reactive protein consistent with suppression of peripheral inflammation. There was no effect on most plasma measures collected. CSF analyses showed nominally significant effects on biomarkers of the core biology of AD; YKL-40 and glial fibrillary acidic protein in CSF were decreased indicating a reduction in astroglial activation. The magnitude of these changes was small (7%-10%) and there was no correlative effect on AD progression. The discrepancy between observations in real world data and the trial outcomes indicates that treatment of symptomatic AD confirmed with biomarkers differs from treatment of patients with diabetes who were cognitively unimpaired and at risk for all cause cognitive decline. The evoke and evoke+ trials suggest that reduction in peripheral inflammation may be insufficient to produce beneficial clinical effects in AD. The results of the evoke(+) trials do not exclude the possibility that AD populations enriched for elevated levels of markers of peripheral inflammation or use of brain penetrant GLP-1 RAs could produce therapeutic benefit.},
}

@article {pmid42785177,
year = {2026},
author = {Mizukami, N and Miwa, K and Umeda, K and Fukuda, T and Takano, N and Hiramoto, M},
title = {Prohibitin 2 mediates the mitochondrial protective effect of the whey-derived tetrapeptide Gly-Thr-Trp-Tyr.},
journal = {Biochemical and biophysical research communications},
volume = {837},
number = {},
pages = {154609},
doi = {10.1016/j.bbrc.2026.154609},
pmid = {42785177},
issn = {1090-2104},
abstract = {Certain dairy products have been reported to reduce the risk of cognitive decline in older adults and patients with Alzheimer's disease (AD). Intake of the whey-derived tetrapeptide Gly-Thr-Trp-Tyr (GTWY) improves mild cognitive impairment in healthy adults, while GTWY administration in mice suppresses AD-like pathologies, including amyloid-beta (Aβ) accumulation and neuroinflammation. GTWY treatment also reduces Aβ-induced mitochondrial dysfunction in neuronal cells. However, the molecular mechanisms underlying these effects remain unclear. Here, we identified prohibitin 2 (PHB2) as a direct binding partner of GTWY in human neuroblastoma SH-SY5Y cells and investigated its role in the mitochondrial protective effect of GTWY. GTWY treatment increased the abundance of the prohibitin complex detected by blue native PAGE without affecting PHB1 or PHB2 expression. Moreover, PHB2 knockdown abolished the mitochondrial protective effect of GTWY, indicating that PHB2 mediates this effect. These findings suggest that GTWY binding to PHB2 modulates the functional state of the prohibitin complex, thereby preserving mitochondrial function. Our results provide new insights into the molecular mechanisms underlying the mitochondrial protective effects of whey-derived peptides and highlight the potential role of the prohibitin complex in mediating these effects.},
}

@article {pmid42785333,
year = {2026},
author = {Mu, R and Hofmann, A and Gong, K and Liu, M and Roussak, A and Lowery, J and Chen, Y and Paczynski, M and Posey, Z and Cheng, Y and Xu, Y and Xie, Y and Powell, WJB and Oh, I and Gupta, A and Sykora, N and Budde, J and Funk, S and Benzinger, TLS and Holtzman, DM and Morris, JC and Snider, BJ and Bateman, RJ and Schindler, SE and Cruchaga, C},
title = {Dynamic changes in plasma biomarkers of Alzheimer's disease in patients treated with lecanemab: a longitudinal cohort study.},
journal = {The Lancet. Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1016/S1474-4422(26)00284-X},
pmid = {42785333},
issn = {1474-4465},
abstract = {BACKGROUND: Anti-amyloid antibodies slow cognitive and functional decline in individuals with early symptomatic Alzheimer's disease, but few studies have examined changes associated with these treatments in plasma biomarkers linked to neurodegeneration. We analysed changes in a panel of 130 plasma proteins and their associations with conversion to amyloid PET negative status and cognitive changes in patients receiving lecanemab infusions as part of their clinical care.

METHODS: This longitudinal cohort study included patients with early symptomatic Alzheimer's disease and positive amyloid biomarkers who were identified as candidates for biweekly lecanemab infusions based on the US Food and Drug Administration label and consented to blood collection at the Washington University Memory Diagnostic Center (St Louis, MO, USA) between July 17, 2023, and Oct 10, 2025. Lecanemab was administered as a 10 mg/kg intravenous infusion every 2 weeks. Patients underwent clinical assessments and blood draws approximately every 6 months over up to 2 years. Research participants enrolled at the Knight Alzheimer Disease Research Center (Knight ADRC; St Louis, MO, USA) between May 3, 1996, and Feb 27, 2025, and who did not receive anti-amyloid antibodies, were included as control groups (an amyloid β-negative [Aβ-] group without cognitive impairment and an untreated group with cognitive impairment). The primary outcome was change in plasma concentrations of protein biomarkers associated with Alzheimer's disease pathology with lecanemab treatment. Associations between plasma biomarker changes and number of lecanemab infusions were examined using regression and mixed-effects models, with adjustment for demographics.

FINDINGS: The study included 197 patients in whom lecanemab infusions had been started (lecanemab group), as well as 173 patients in whom lecanemab had been ordered but not yet started, who were combined with 1139 research participants with cognitive impairment from the Knight ADRC cohort to form the untreated control group with cognitive impairment (n=1312). An additional 458 research participants formed the Aβ- control group without cognitive impairment. In the lecanemab group, the median patient age was 73 years (IQR 69-77); 104 (53%) were female and 93 (47%) were male; and most participants were White (187 [98%] of 190 with available data) and non-Hispanic (183 [97%] of 188 with available data). 130 biomarkers were classified into four distinct trajectories, with 34 showing significant changes (false discovery rate <0·05) in the lecanemab group. The trajectories were: normalising, with biomarkers shifting towards concentrations found in Aβ-individuals without cognitive impairment (eg, phosphorylated tau [p-tau]217, MAPT, and GFAP); overcorrecting, with biomarkers shifting towards and then beyond concentrations found in Aβ- individuals without cognitive impairment (eg, amyloid β peptides); opposite, with biomarkers shifting further from concentrations found in Aβ- individuals without cognitive impairment (eg, NPTXR, NRGN, and TREM2); and unchanged (eg, NEFL and APOE).

INTERPRETATION: Lecanemab treatment was associated with dynamic, multidirectional changes across plasma biomarkers of Alzheimer's disease pathology, with partial normalisation of amyloid and tau biomarkers alongside abnormal concentrations of inflammatory and neurodegeneration-related biomarkers (eg, TREM2 and NPTXR), which might reflect an immune response to amyloid plaques and effects of treatment on neuronal and synaptic processes distinct from amyloid clearance. These divergent trajectories suggest that different biomarkers could eventually serve different clinical purposes, such as monitoring treatment response or informing patient prognosis, although further validation is needed.

FUNDING: National Institute on Aging, Cure Alzheimer's Fund, and Washington University.},
}

@article {pmid42785896,
year = {2026},
author = {Priya, and Mittal, R and Banerjee, J and Dixit, A},
title = {Blood-based biomarkers in Alzheimer's and Parkinson's disease: From molecular pathology to therapeutic potential.},
journal = {International review of neurobiology},
volume = {191},
number = {},
pages = {225-273},
doi = {10.1016/bs.irn.2026.02.006},
pmid = {42785896},
issn = {2162-5514},
mesh = {Humans ; *Parkinson Disease/blood/therapy/pathology ; *Biomarkers/blood ; *Alzheimer Disease/blood/pathology/therapy ; *alpha-Synuclein/blood ; Animals ; Amyloid beta-Peptides/blood ; Pathology, Molecular ; tau Proteins/blood ; },
abstract = {Alzheimer's (AD) and Parkinson's disease (PD) represent a major class of neurodegenerative disorders characterized by different proteinopathies with amyloid-β plaques and tau tangles in AD, while α-synuclein containing Lewy bodies in PD, specific molecular signatures. Alongside this central mechanism, they share pathological cascades including axonal degeneration, synaptic dysfunction, glial activation and neuroinflammation. The emergence of blood-based biomarkers, represents a paradigm shift in the field of diagnosis and therapeutics by addressing these core pathological mechanism of central nervous system. This chapter highlights a overview of blood-based biomarkers emerging in the field of AD and PD, exploring the clinical utility of core pathology markers (Aβ42/40, p-tau species, and α-synuclein), alongside other neurodegenerative markers such as neurofilament light chain and glial activation markers like GFAP. Beyond the diagnosis, we emphasize on the potential role of blood-based biomarkers as a surrogate and pharmacodynamic endpoint in disease modifying clinical trial development, facilitating dose optimization and target engagement. Future prospects empathize on the use of multimodal approach integration, trajectory modeling and novel target discovery. Collectively, these blood-based biomarkers enable transition of neurodegenerative disorders treatment from symptom-based classification to towards a mechanism targeted therapeutic framework.},
}

Humans
*Parkinson Disease/blood/therapy/pathology
*Biomarkers/blood
*Alzheimer Disease/blood/pathology/therapy
*alpha-Synuclein/blood
Animals
Amyloid beta-Peptides/blood
Pathology, Molecular
tau Proteins/blood

@article {pmid42785901,
year = {2026},
author = {Rajesh, N and R, J and Joji, R and Sivakumar, S and Francis, D},
title = {Neurofilament light chain (NfL) as a biomarker for neurodegeneration: Protein biology, detection methods, and clinical applications.},
journal = {International review of neurobiology},
volume = {191},
number = {},
pages = {447-485},
doi = {10.1016/bs.irn.2026.05.009},
pmid = {42785901},
issn = {2162-5514},
mesh = {Humans ; Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Neurofilament Proteins/metabolism ; Animals ; *Intermediate Filaments/metabolism ; },
abstract = {Neurofilaments are vital structural components of neurons and play a central role in preserving axonal architecture and function. Among these, neurofilament light chain (NfL) has emerged as a sensitive biomarker of neuroaxonal injury. This chapter delineates the molecular organisation of neurofilaments, tracing their hierarchical assembly from coiled-coil dimers to mature filaments, and emphasises their contribution to axonal stability, calibre regulation, and intracellular transport. It further examines how perturbations in neurofilament homeostasis reflect neuronal damage across a broad spectrum of neurological disorders. Advances in analytical technologies, particularly ultrasensitive immunoassays such as Sioma and ELISA, have enabled robust quantification of NfL in cerebrospinal fluid and blood, facilitating its translation from experimental research into clinical practice. The diagnostic and prognostic relevance of NfL is examined across neurodegenerative, inflammatory, traumatic, and vascular diseases of the nervous system, with particular focus on Alzheimer's and Parkinson's diseases, highlighting its utility for disease monitoring and assessing treatment response. A discussion of clinical factors to consider when assessing NfL for disease diagnosis, along with its current challenges, is provided to draw attention to additional research. Through mechanistic insights spanning protein biology, clinical findings, and biomarker science, this chapter highlights NfL as a robust and non-invasive indicator of neuroaxonal injury applicable across distinct aetiologies. It posits that the systematic incorporation of NfL measurements into clinical workflows may refine nosological classification, enhance diagnostic and prognostic precision, and improve risk stratification at both individual and cohort levels, whilst informing evidence-based therapeutic decision-making and longitudinal patient management across a wide spectrum of neurological conditions.},
}

Humans
Biomarkers/metabolism
*Neurodegenerative Diseases/diagnosis/metabolism
*Neurofilament Proteins/metabolism
Animals
*Intermediate Filaments/metabolism

@article {pmid42785906,
year = {2026},
author = {Eliazer, GR and Kandasamy, M},
title = {Circulating biochemical signatures of neurodegeneration in Alzheimer's disease.},
journal = {International review of neurobiology},
volume = {191},
number = {},
pages = {91-111},
doi = {10.1016/bs.irn.2026.06.004},
pmid = {42785906},
issn = {2162-5514},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; Animals ; },
abstract = {Alzheimer's Disease (AD), a major cause of progressive memory loss, is pathogenically associated with the accumulation of amyloid-beta (Aβ) plaques, tau-mediated neurofibrillary tangles, neuroinflammation, and neurodegeneration. The molecular, biochemical and cellular malformation apears to occur before the onset of behavioural symptoms and intensifies as the disease progresses, highlighting the importance of early diagnostic approaches. The routine neuroimaging-based techniques, such as magnetic resonance imaging and positron emission tomography, are highly valuable to monitor the emergence of symptoms but are limited by high cost and accessibility. The cerebrospinal fluid-based methods provide valuable insight into the state of disease, however the procedure associated with sample collection is highly invasive. Eventually, the blood-based biomarkers have emerged as a promising and minimally invasive alternative procedure for the detection and monitoring of AD. The circulating biomarkers such as Aβ , phosphorylated tau isoforms, and associated abnormal biochemical signatures are correlated with pathological processes in AD. Assessing these blood biomarkers is not only crucial for diagnostics but also important for monitoring the changes associated with treatment in AD. As most current treatment options provide only symptomatic relief, advanced diagnostic approaches are essential for early detection and therapeutic intervention. The blood-based biomarkers represent a transformative step toward early diagnosis, large-scale screening, and precision medicine in AD, with significant potential for the development of disease-modifying therapies. Thus, this book chapter provides an overview of blood-based biomarker panels and discusses recent advances in bioanalytical technologies in AD.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
*tau Proteins/blood
*Amyloid beta-Peptides/blood
Animals

@article {pmid42786742,
year = {2026},
author = {Meng, J and Wang, Y and Wang, J and Chen, Y and Zhao, Z and Tang, Z and Cao, J and Zhang, X and Luo, H and Li, H and Wu, Y and Zhao, Y and Song, W and Zhang, YW},
title = {TMEM59 regulates microglial Aβ phagocytosis in a TREM2-dependent manner and acts as a potential therapeutic target for Aβ amyloidosis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71873},
doi = {10.1002/alz.71873},
pmid = {42786742},
issn = {1552-5279},
support = {82588301//National Natural Science Foundation of China/ ; U25A2072//National Natural Science Foundation of China/ ; 82501698//National Natural Science Foundation of China/ ; 82371420//National Natural Science Foundation of China/ ; 2025M782230//China Postdoctoral Science Foundation/ ; 2025B-07-39//Changping Laboratory/ ; },
mesh = {Animals ; *Microglia/metabolism ; *Membrane Glycoproteins/metabolism/genetics ; *Phagocytosis/physiology ; *Receptors, Immunologic/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Membrane Proteins/metabolism/genetics ; Mice ; *Alzheimer Disease/metabolism/genetics/pathology ; Mice, Transgenic ; *Amyloidosis/metabolism ; *Nerve Tissue Proteins/metabolism/genetics ; Disease Models, Animal ; Plaque, Amyloid/metabolism/pathology ; },
abstract = {INTRODUCTION: Microglia-mediated clearance of amyloid beta (Aβ) is crucial for mitigating Alzheimer's disease (AD) progression, yet the molecular regulators of microglial phagocytosis remain incompletely understood.

METHODS: We assessed AD-related phenotypes in 5xFAD mice with microglia-specific deletion of transmembrane protein 59 (TMEM59). Microglial transcriptomic profiling was performed using single-cell RNA sequencing (scRNA-seq). A chaperone-mediated autophagy-targeting chimera (CMATAC) peptide was developed to degrade TMEM59, and its therapeutic efficacy was evaluated.

RESULTS: Microglia-specific TMEM59 ablation attenuated cognitive deficits, Aβ plaque burden, and synapse loss in 5xFAD mice. TMEM59 deficiency reprogrammed disease-associated microglia toward a highly phagocytic state. Mechanistically, TMEM59 deficiency enhanced microglial Aβ phagocytosis in a triggering receptor expressed on myeloid cells 2 (TREM2)-dependent manner, as it stabilized TREM2 protein, whereas loss of TREM2 abolished these protective effects. Treatment with the TMEM59-degrading CMATAC peptide alleviated behavioral deficits and enhanced microglial Aβ phagocytosis in 5xFAD mice.

DISCUSSION: TMEM59 is a key regulator of microglial phagocytosis in AD and a novel target for amyloidosis intervention.},
}

Animals
*Microglia/metabolism
*Membrane Glycoproteins/metabolism/genetics
*Phagocytosis/physiology
*Receptors, Immunologic/metabolism/genetics
*Amyloid beta-Peptides/metabolism
*Membrane Proteins/metabolism/genetics
Mice
*Alzheimer Disease/metabolism/genetics/pathology
Mice, Transgenic
*Amyloidosis/metabolism
*Nerve Tissue Proteins/metabolism/genetics
Disease Models, Animal
Plaque, Amyloid/metabolism/pathology

@article {pmid42786847,
year = {2026},
author = {Yu, Y and Xu, Y and Xu, M},
title = {Therapeutic Strategies Targeting TREM2 for Alzheimer's Disease: Current Advances and Future Perspectives.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X509125260907101247},
pmid = {42786847},
issn = {1875-6190},
abstract = {BACKGROUND: Alzheimer's disease is a progressive neurodegenerative disorder characterized by cognitive decline and protein aggregation. The Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) has been identified as a key regulator of pathogenesis. This review summarizes current understanding of the receptor's structure, ligands, signaling, roles in disease, and therapeutic targeting strategies.

METHODS: A structured narrative review was conducted using targeted searches of PubMed, Web of Science, and Scopus, supplemented by citation tracking and searches of ClinicalTrials.gov.

RESULTS: TREM2 is a microglial immunoreceptor that recognizes apolipoprotein E and amyloid-β. Through the canonical DAP12-SYK axis, TREM2 regulates microglial phagocytosis, metabolism, and inflammatory responses. In Alzheimer's disease, it modulates amyloid-β clearance, tau hyperphosphorylation, and neuroinflammation in a stage-dependent manner. Loss-of-function variants increase disease risk. Therapeutic strategies include direct membrane-TREM2 agonistic antibodies, shedding-modifying antibody fragments, soluble TREM2-based approaches, gene-delivery platforms, small-molecule agonists, and indirect TREM2-associated natural-product modulators. These approaches differ in target-binding evidence, TREM2 dependence, disease-model relevance, safety, and clinical maturity.

DISCUSSION: TREM2 functions within a context-dependent framework in which gene dosage, disease stage, pathological substrate, microglial state, and activation duration jointly determine protective or maladaptive outcomes. Therapeutic modalities differ in specificity, brain exposure, reversibility, and translational readiness, while target engagement alone does not guarantee clinical benefit.

CONCLUSIONS: TREM2 remains a promising but context-sensitive therapeutic target. Successful translation will require controllable modulation, stage- and pathology-specific treatment windows, biomarkers of functional response, and patient stratification according to genotype, amyloid-β and tau burden, and microglial state.},
}

@article {pmid42787519,
year = {2026},
author = {Zaic, S and König, T and Keritam, O and Faber, V and Seifried, K and Silvaieh, S and Krajnc, N and Wurm, R and Parvizi, T and Macher, S and Rommer, P and Leutmezer, F and Bsteh, G and Stögmann, E and Berger, T and Zrzavy, T},
title = {Cerebrospinal fluid protein elevations in Alzheimer's disease are dissociated from immune cell composition.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70321},
pmid = {42787519},
issn = {2352-8737},
abstract = {INTRODUCTION: Elevated cerebrospinal fluid (CSF) inflammatory proteins have been reported in Alzheimer's disease (AD), yet whether they reflect peripheral immune cell infiltration or central nervous system (CNS)-intrinsic pathological processes remains unclear. We tested whether AD exhibits a distinct CSF protein signature and how it relates to CSF immune cell composition.

METHODS: We conducted a cross-sectional study of 64 participants: 22 with biomarker-confirmed AD (bioAD), 22 non-AD biomarker-negative cognitive controls (NAD-CC), and 20 other neurological disease controls (OND). CSF proteins were quantified using the Olink Target 96 Inflammation panel, and immune cell populations were characterized by multiparameter spectral flow cytometry. Cell-protein associations were assessed using hierarchical generalized linear models adjusted for age and sex.

RESULTS: BioAD showed widespread inflammatory and trophic protein elevation versus NAD-CC, with 21 proteins significantly increased (false discovery rate [FDR] q < 0.05), whereas NAD-CC was largely indistinguishable from OND. MMP-10 showed the largest effect (geometric mean ratio [GMR] = 2.10, 95% confidence interval [CI]: 1.53-2.88, p < 0.001). CSF immune cell populations did not differ significantly between groups; only discrete T-cell alterations were detected: reduced regulatory T cells in bioAD relative to NAD-CC (odds ratio [OR] = 0.69, 95% CI: 0.54-0.88, p = 0.023), but not relative to OND and minor memory subset shifts. CD8+ effector memory T cells and TNFSF14 showed the only detected AD-specific association: in bioAD, a 10-fold increase in CD8+ EM2 cells corresponded to 70% higher TNFSF14 (GMR = 1.70, 95% CI: 1.39-2.09, p < 0.0001).

DISCUSSION: In this feasibility-sized, cross-sectional cohort, CSF inflammatory proteins in AD appeared dissociated from immune-cell composition, potentially reflecting CNS-intrinsic processes and/or altered CSF barrier dynamics. The identified signature, including MMP-10, is hypothesis-generating and may complement conventional biomarkers for diagnosis and treatment monitoring, pending longitudinal validation.},
}

@article {pmid42787809,
year = {2026},
author = {Shimasaki, R and Kurihara, M and Sato, K and Bannai, T and Hatano, K and Ishii, K and Ihara, R and Ogawa, S and Iwata, A},
title = {Clinical utility of LUMIPULSE plasma p-tau217 to identify amyloid positivity among candidates for amyloid-targeting treatments in a real-world cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70497},
pmid = {42787809},
issn = {2352-8729},
abstract = {INTRODUCTION: Increasing clinical use of amyloid-targeting treatments (ATTs) requires accessible biomarkers for Alzheimer's disease (AD). Although the utility of plasma phosphorylated tau 217 (p-tau217) is well established in research cohorts and its use for identifying amyloid positivity among ATT candidates is expanding into clinical practice, real-world evidence of its performance is lacking.

METHODS: We evaluated the utility of LUMIPULSE plasma p-tau217 in a real-world cohort of 99 patients screened for ATT eligibility.

RESULTS: Amyloid positivity was confirmed in 82 (82.8%) patients. Plasma p-tau217 predicted amyloid status, with an area under the curve of 0.93. With a cutpoint (0.1795 pg/mL) based on the Youden index, this approach achieved 95.1% sensitivity, 94.1% specificity, 98.7% positive predictive value, and 80.0% negative predictive value (NPV). Higher external thresholds led to a lower NPV, demonstrating that cut points must be optimized for clinical stages.

DISCUSSION: These findings provide real-world evidence supporting the clinical utility of p-tau217 for ATT candidates.},
}

@article {pmid42788819,
year = {2026},
author = {Busquets, MA and Sabaté, R and Álvarez-Berbel, I and Espargaró, A},
title = {Applications of Prussian blue nanoparticles in the treatment of neurodegenerative diseases.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/17435889.2026.2734070},
pmid = {42788819},
issn = {1748-6963},
abstract = {Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are characterized by progressive neuronal dysfunction associated with oxidative stress, chronic neuroinflammation, mitochondrial impairment, and pathological protein aggregation. Despite advances in symptomatic treatments, effective disease-modifying therapies remain limited. This review examines the emerging role of Prussian blue nanoparticles (PBNPs) as multifunctional nanoplatforms for neurodegenerative diseases and related neurological conditions, including ischemic stroke and nerve regeneration. Their intrinsic enzyme-mimetic (nanozyme) activities enable the catalytic scavenging of reactive oxygen and nitrogen species, mimicking key antioxidant enzymes such as superoxide dismutase and catalase. PBNPs may also modulate neuroinflammation, microglial activation, and the aggregation of neurotoxic proteins, including β-amyloid and α-synuclein. Advances in nanoparticle engineering to improve brain delivery, targeting, and pharmacokinetics are highlighted. Finally, the review critically addresses toxicological challenges, including biodistribution, organ accumulation, degradation, long-term persistence, and the potential effects of surface modifications, which remain key considerations for the safe clinical translation of PBNP-based therapeutic and theranostic strategies.},
}

@article {pmid42790169,
year = {2026},
author = {Zhang, B and Nan, J and Zhang, Y and Zhang, B and Ke, C and Wang, W and Wu, T and Xia, J and Yang, F and He, M and Tian, L and Yang, Z and Liang, C},
title = {Phytocannabinoid cannabidiol (CBD) in neurodegenerative diseases: From polypharmacology to drug development.},
journal = {European journal of medicinal chemistry},
volume = {320},
number = {},
pages = {119360},
doi = {10.1016/j.ejmech.2026.119360},
pmid = {42790169},
issn = {1768-3254},
abstract = {Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has attracted interest as a multi-target neurotherapeutic candidate for neurodegenerative diseases. CBD is a lipophilic terpenophenolic chemotype whose phenolic redox chemistry, membrane partitioning, cytochrome P450-mediated metabolism, and formulation-dependent exposure are central to its biological activity and translational limitations. In addition, CBD engages a broad target network relevant to neurodegeneration. Major components include cannabinoid receptors, transient receptor potential channels, peroxisome proliferator-activated receptor-γ, adenosine and serotonin signaling systems, voltage-gated calcium channels, and redox-regulatory pathways. These mechanisms converge on neuroinflammation, excitotoxicity, mitochondrial dysfunction, impaired proteostasis, and synaptic injury. Preclinical studies across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis consistently support CBD's anti-inflammatory, antioxidant, mitochondria-protective, and neuroprotective pharmacology. The magnitude of these effects depends on dose, treatment timing, model system, and route of administration. Clinical evidence remains preliminary and is mainly symptomatic, with signals in agitation, sleep disturbance, spasticity, quality of life, and neuropsychiatric symptoms rather than proven disease modification. Key barriers to development include low and variable oral bioavailability, incomplete brain exposure data, uncertain active metabolite contributions, limited target-engagement biomarkers, and insufficient exposure-response definition. Future development of CBD and optimized cannabinoid-derived analogues will require medicinal chemistry strategies to improve potency, selectivity, metabolic stability, CNS exposure, and formulation performance. Parallel biomarker-driven clinical trials are needed to define pharmacokinetic-pharmacodynamic relationships and evaluate disease-modifying potential.},
}

@article {pmid42790767,
year = {2026},
author = {Bi, H and Sun, M and Ma, Q and Li, X and Wang, Y},
title = {RNA m6A demethylase FTO in central nervous system disorders: Mechanisms and therapeutic implications.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111942},
doi = {10.1016/j.pnpbp.2026.111942},
pmid = {42790767},
issn = {1878-4216},
abstract = {The fat mass and obesity-associated protein (FTO) is an obesity-related protein that is widely expressed in different tissues throughout the human body, with relatively high expression levels observed in the brain. Initial investigations into FTO mainly concentrated on its involvement in the development of obesity and diabetes. However, accumulating evidence has subsequently identified FTO as an N6-methyladenosine (m6A) demethylase, suggesting that it may participate in various neurological processes, including neural differentiation, synaptic plasticity, and neuroinflammation, through modulation of RNA m6A methylation. Increasing studies have demonstrated that FTO is involved in the pathophysiological mechanisms and therapeutic responses of a range of central nervous system (CNS) disorders, including Parkinson's disease, epilepsy, Alzheimer's disease, stroke, brain tumors, depression, autism, and substance use disorders. This review summarizes the potential roles of FTO in the pathogenesis and treatment of CNS disorders, with the aim of providing novel perspectives and potential therapeutic targets for further research and clinical intervention in CNS diseases.},
}

@article {pmid42791463,
year = {2026},
author = {Li, Z and Liu, Z and Zhang, Y and Lei, Y and Wang, Y},
title = {Brain-Wide Multi-Trait Genetic Integration Implicates Lysosomal and Metabolic Axes Linking Visual Disturbance and Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42791463},
issn = {1559-1182},
mesh = {*Alzheimer Disease/genetics/metabolism/complications ; Humans ; *Brain/metabolism/pathology ; Genome-Wide Association Study ; *Lysosomes/metabolism/genetics ; *Vision Disorders/genetics/metabolism/complications ; *Genetic Predisposition to Disease ; *Quantitative Trait, Heritable ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; },
abstract = {Visual impairment has been proposed as a potentially modifiable risk factor for dementia, including Alzheimer's disease (AD), but the biological mechanisms linking visual disturbance to AD remain unclear. It is unknown whether AD and visual disturbance share specific genetic determinants, how such effects are distributed across brain regions, and whether they converge on discrete molecular pathways that could be targeted for prevention or treatment. Multi-trait analysis of GWAS was applied to summary statistics from large-scale GWAS of AD and a visual disturbance (VD) phenotype, yielding VD-informed AD association statistics (VDAD). Gene-level associations were then mapped across brain tissues by integrating single-tissue and cross-tissue transcriptome-wide association studies, brain proteome-wide association analyses and gene-based tests. A small set of genes (GRN, PVR and RAB29) emerged as consistently associated with both AD and VDAD. A broader panel of genes showed partially overlapping but also phenotype-specific architectures, with PM20D1 and LRRC37A2 more prominent in AD and SLC41A1 and MTCH2 more strongly implicated in VDAD. These signals were anchored to frontal cortical, hippocampal, cerebellar and striatal tissues, suggesting involvement of circuits that integrate visual input with memory, motor control and balance. Network and pathway analyses highlighted a GRN-centered lysosomal axis and metabolic pathways linked to PM20D1 and SLC41A1 as candidate mechanisms bridging visual disturbance and AD risk. These findings support the view that visual disturbance-related AD risk is shaped by a limited set of genes and pathways that are supported across complementary molecular analyses and mapped to distributed brain/CNS reference tissues. These findings generate testable hypotheses for future studies with detailed visual phenotyping.},
}

*Alzheimer Disease/genetics/metabolism/complications
Humans
*Brain/metabolism/pathology
Genome-Wide Association Study
*Lysosomes/metabolism/genetics
*Vision Disorders/genetics/metabolism/complications
*Genetic Predisposition to Disease
*Quantitative Trait, Heritable
Phenotype
Polymorphism, Single Nucleotide/genetics

@article {pmid42791497,
year = {2026},
author = {Nevyhoštěná, M and Komersová, A and Svoboda, R and Pejchal, V and Pospíšilová, A and Muselík, J and Łapa, A and Koczurkiewicz-Adamczyk, P},
title = {Personalized 3D-Printed Affinisol-Based Pharmaceutical Delivery Systems: The Case Study for Alternative Sulfonamides for Alzheimer's Disease.},
journal = {Macromolecular bioscience},
volume = {26},
number = {9},
pages = {e70266},
doi = {10.1002/mabi.70266},
pmid = {42791497},
issn = {1616-5195},
support = {SGS_2026_006//Internal Grant Agency of the University of Pardubice/ ; },
mesh = {*Printing, Three-Dimensional ; *Alzheimer Disease/drug therapy/pathology ; Humans ; *Sulfonamides/chemistry/pharmacology/therapeutic use/pharmacokinetics ; Tablets ; Solubility ; *Precision Medicine ; *Drug Delivery Systems ; Drug Liberation ; },
abstract = {The use of hot melt extrusion combined with fused deposition modeling 3D printing was explored to enhance the solubility and bioavailability of poorly water-soluble compounds intended for Alzheimer's disease (AD) therapy. AD, a neurodegenerative disorder with no definitive treatment, affects millions worldwide, underscoring the urgent need for effective and personalized therapeutic strategies. Four sulfonamide-derived compounds, identified as potential AD therapeutics, were synthesized and successfully incorporated (loads between 10 and 50 wt.%) into customized, 3D-printed oral dosage forms. These 3D-printed tablets were evaluated for properties such as hardness, thermo-analytical characterization, dissolution, cytotoxicity, and stability. Notably, successful amorphization of the incorporated APIs was observed in most 3D-printed tablets, which may be critical for improving solubility. In vitro dissolution testing revealed multiple favorable release profiles, with several formulations demonstrating sustained or enhanced drug release suitable for the therapeutic requirements of AD. When compared to the dissolution data of the corresponding conventional matrix tablets, the present 3D-printed tablets offered superior or comparable dissolution characteristics, demonstrating the potential of personalized medicine and remote digital control for optimizing patient-specific treatments.},
}

*Printing, Three-Dimensional
*Alzheimer Disease/drug therapy/pathology
Humans
*Sulfonamides/chemistry/pharmacology/therapeutic use/pharmacokinetics
Tablets
Solubility
*Precision Medicine
*Drug Delivery Systems
Drug Liberation

@article {pmid42793309,
year = {2026},
author = {Narasimhappagari, J and Liu, L and Griffin, WST},
title = {Interleukin-1β-Induced Inflammatory Signaling and Myelin-Related Alterations in Oligodendroglia and Schwann Cells in Multiple Sclerosis: Modulatory Effects of Ibuprofen and Flurbiprofen.},
journal = {Current issues in molecular biology},
volume = {48},
number = {9},
pages = {},
doi = {10.3390/cimb48090953},
pmid = {42793309},
issn = {1467-3045},
support = {1R01AR084472-04/NH/NIH HHS/United States ; },
abstract = {Neuroinflammation, read as elevated levels of Interleukin-1β (IL-1β) and of its downstream signaling cascade, has been shown to play a neuropathogenic role in numerous neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Western blotting was used to determine the effects of IL-1β and its signaling cascade on Human Oligodendroglioma (HOG) and Schwann cells and to evaluate the potential therapeutic effects of Ibuprofen and Flurbiprofen on MS pathogenesis in vitro. IL-1β increased neuroinflammatory markers like TNFα, MyD88, βAPP, COX-2, and IL-6, as well as transcription factors like NFκB and STAT in HOG and Schwann cells, which in turn regulate the expression of other cytokines, resulting in the activation of the self-perpetuating Cytokine Cycle. The IL-1β treatment of HOG and Schwann cells decreased the levels of myelin Basic Protein (MBP) and synaptophysin while at the same time increasing βAPP. Autophagy markers like LAMP-2 and LC3B were downregulated. In contrast, treatment with Ibuprofen and Flurbiprofen effectively countered the harmful effects of IL-1β in MS. These in vitro studies show that IL-1β can play a possible detrimental role in facilitating neuropathogenesis, as seen in Alzheimer's and Parkinson's disease, and anti-inflammatory drugs Ibuprofen and Flurbiprofen have a potential role in modulating the neuroinflammation in MS.},
}

@article {pmid42793338,
year = {2026},
author = {Yang, Y and Kim, J and Kang, Y and Choi, S and Seo, J and Kim, S},
title = {Short-Term Cognitive and Behavioral Changes After Low-Intensity Transcranial Ultrasound Stimulation in Early Alzheimer's Disease: An IPTW-Adjusted Retrospective Exploratory Comparative Study.},
journal = {Brain sciences},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/brainsci16090913},
pmid = {42793338},
issn = {2076-3425},
support = {//Deepson Bio, Ltd/ ; },
abstract = {Background: Low-intensity ultrasound (LIUS) has been proposed as a non-invasive approach to modulate cerebrospinal fluid movement, glymphatic-lymphatic clearance, and amyloid-beta (Aβ) handling in Alzheimer's disease (AD). However, clinical comparisons in amyloid biomarker-confirmed patients receiving standard pharmacotherapy remain limited, and the short-term cognitive domains most likely to change after LIUS remain uncertain. Objective: The objective of this study was to compare 4-week changes in cognitive function, executive function, quality of life, and neuropsychiatric symptoms between amyloid PET-positive patients receiving add-on LIUS with donepezil-based standard treatment and those receiving donepezil-based standard treatment alone. Methods: This retrospective exploratory comparative cohort study included amyloid PET-positive patients with mild cognitive impairment or early AD who received donepezil-based standard treatment. The treatment cohort received 4 weeks of add-on LIUS at Dongtan or Bundang centers, whereas the comparator cohort received donepezil-based standard treatment alone at Soonchunhyang. Outcomes were changes from baseline to 4 weeks in Trail Making Test A (TMT-A), Trail Making Test B (TMT-B), Mini-Mental State Examination, Second Edition (MMSE-II), Quality of Life in Alzheimer's Disease (QoL-AD), and Neuropsychiatric Inventory (NPI). Group differences were examined using unadjusted change-score comparisons and stabilized inverse probability of treatment weighting (IPTW). Results: The full analysis set included 51 amyloid PET-positive participants receiving donepezil-based standard treatment: 20 who additionally received LIUS and 31 who received standard treatment alone. Compared with controls, the add-on LIUS group showed greater improvement in TMT-A completion time in unadjusted analysis (-20.0 ± 31.3 s vs. -0.1 ± 5.6 s; p = 0.011), and this association remained significant after IPTW adjustment. TMT-B showed a favorable but less robust pattern, with borderline findings in the primary Fail-excluded analyses and a significant result in the Fail = 300 sensitivity analysis. MMSE-II change did not differ between groups. NPI improved more in the add-on LIUS group in unadjusted analysis, although this finding was exploratory. Conclusions: In amyloid PET-positive patients receiving donepezil-based standard treatment, 4 weeks of add-on LIUS was associated with short-term improvement in TMT-A performance compared with standard treatment alone, while MMSE-II remained unchanged. The findings suggest a preliminary signal for processing-speed or visual-search improvement and support prospective randomized sham-controlled studies with harmonized cognitive testing and biomarker endpoints.},
}

@article {pmid42793674,
year = {2026},
author = {Pyrgelis, ES and Paraskevas, GP and Constantinides, VC and Boufidou, F and Stefanis, L and Kapaki, E},
title = {α-Synuclein Pathology in Idiopathic Normal Pressure Hydrocephalus: Evidence for Concomitant Synucleinopathy and Clinical Implications.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {18},
pages = {},
doi = {10.3390/diagnostics16182889},
pmid = {42793674},
issn = {2075-4418},
support = {Grant 2018 E01300001//General Secretariat of Research and Innovation/ ; },
abstract = {Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterized by gait impairment, cognitive decline, and urinary dysfunction. Despite improvements in diagnostic criteria and neuroimaging techniques, accurate diagnosis remains challenging due to clinical overlap with neurodegenerative diseases, particularly Alzheimer's disease (AD) and synucleinopathies. Biomarkers capable of improving differential diagnosis, patient selection for shunt surgery, and prognostic assessment are therefore of considerable clinical interest, as has been in AD biomarkers. This review summarizes current evidence regarding the role of α-synuclein as a potential additional marker in iNPH, focusing on its association with concomitant neurodegenerative pathology, clinical manifestations, and treatment outcomes. Available studies indicate that α-synuclein pathology may coexist with iNPH in a substantial proportion of patients, with reported positivity rates ranging from approximately 14% to 33%, depending on the detection method used. Patients with concomitant α-synuclein pathology may exhibit clinical features atypical for pure iNPH, including upper limb rigidity, olfactory dysfunction, hallucinations, autonomic dysfunction, sleep disturbances, and fluctuating cognitive impairment. However, current evidence does not support α-synuclein positivity as an independent predictor of poor response to cerebrospinal fluid (CSF) drainage or shunt surgery. On the contrary, α-synuclein presence may provide additional information regarding mixed neurodegenerative pathology and contribute to personalized clinical management. Future studies should focus on standardized detection techniques, larger multicenter cohorts, longitudinal follow-up, and integration of α-synuclein assessment with established AD biomarkers, neuroimaging findings, and clinical evaluation. Overall, α-synuclein represents a promising complementary marker in iNPH, with potential value in being taken into consideration during clinical evaluation and understanding disease heterogeneity.},
}

@article {pmid42794551,
year = {2026},
author = {Procopciuc, LM and Hangan, AC and Gog-Bogdan, S and Lucaciu, RL},
title = {The Tryptophan-Kynurenine Pathway as a Key Mediator of the Gut-Brain Axis in Depression and Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188122},
pmid = {42794551},
issn = {1422-0067},
mesh = {Humans ; *Kynurenine/metabolism ; *Tryptophan/metabolism ; *Alzheimer Disease/metabolism/microbiology ; *Depression/metabolism ; Animals ; Gastrointestinal Microbiome ; *Brain/metabolism ; *Brain-Gut Axis ; Signal Transduction ; },
abstract = {Depression and Alzheimer's disease are among the most prevalent and disabling disorders worldwide, imposing a substantial social, economic, and healthcare burden. Increasing evidence suggests that these conditions share several pathophysiological mechanisms, including chronic inflammation, oxidative stress, mitochondrial dysfunction, altered neurotransmission, and gut microbiota dysbiosis. In recent years, the microbiota-gut-brain axis has emerged as a key regulatory system linking gastrointestinal, immune, metabolic, and neural functions. Within this complex network, the tryptophan-kynurenine pathway has gained considerable attention as a critical mediator connecting gut microbial activity, immune responses, and central nervous system function. This review examines the role of the microbiota-gut-brain axis and the tryptophan-kynurenine pathway in the development and progression of depression and Alzheimer's disease. Particular emphasis is placed on the regulation of tryptophan metabolism by gut microbiota, the inflammatory activation of indoleamine 2,3-dioxygenase, and the generation of neuroactive kynurenine metabolites. Dysregulation of these processes may reduce serotonin synthesis while promoting the accumulation of neurotoxic compounds such as quinolinic acid and 3-hydroxykynurenine, thereby contributing to neuroinflammation, excitotoxicity, cognitive decline, and depressive symptoms. Current evidence also highlights the therapeutic potential of interventions targeting gut microbiota composition and kynurenine pathway activity. A better understanding of these interconnected mechanisms may facilitate the identification of novel biomarkers and the development of personalized strategies for the prevention and treatment of both psychiatric and neurodegenerative disorders.},
}

Humans
*Kynurenine/metabolism
*Tryptophan/metabolism
*Alzheimer Disease/metabolism/microbiology
*Depression/metabolism
Animals
Gastrointestinal Microbiome
*Brain/metabolism
*Brain-Gut Axis
Signal Transduction

@article {pmid42794584,
year = {2026},
author = {Paul, PS and Borenstein-Katz, A and Shmeit, K and Wille, H and Kar, S},
title = {Attenuation of Tau-Mediated β-Amyloid1-42 Aggregation by Native PLGA Nanoparticles and Its Relevance to Alzheimer Disease Pathology.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188152},
pmid = {42794584},
issn = {1422-0067},
support = {RES0035124//Alzheimer Society of Canada and Northwest Territories/ ; MOP-84480/CAPMC/CIHR/Canada ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; *tau Proteins/metabolism/chemistry ; *Alzheimer Disease/metabolism/pathology ; *Nanoparticles/chemistry ; *Peptide Fragments/metabolism/chemistry ; *Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Humans ; Protein Aggregates/drug effects ; Animals ; *Protein Aggregation, Pathological/metabolism ; },
abstract = {Alzheimer's disease (AD) is an unremitting neurodegenerative disorder characterized by the presence of extracellular β-amyloid (Aβ)-containing neuritic plaques, intracellular tau-positive neurofibrillary tangles and loss of selected neurons in the brain. Evidence suggests that aggregation of Aβ and tau via synergistic interactions initiates a cascade of events, leading to development of AD pathology. Thus, many studies are being pursued to develop small molecules/drugs that can target both Aβ and tau as an effective AD treatment strategy. In this study, we evaluated effects of native PLGA nanoparticles on tau-mediated Aβ1-42 aggregation using biophysical, structural, spectroscopic and biochemical approaches. Our results show that 0N4R tau seeds enhanced Aβ1-42 aggregation, and that this effect is mitigated by native PLGA. Additionally, PLGA inhibited Aβ1-42 aggregation induced by both 0N4R and 2N4R tau isoforms. The presence of PLGA during the formation of tau seeds or pretreatment of tau seeds with PLGA attenuates subsequent Aβ1-42 aggregation. Interestingly, monomeric 0N4R tau, unlike 0N4R tau seeds, suppressed Aβ1-42 aggregation, which is diminished further by PLGA nanoparticles. However, we have not addressed the implications of native PLGA on tau/Aβ1-42 interaction using any cellular or animal models of AD. Nevertheless, our results reveal that tau seeds and monomeric tau can differentially influence Aβ1-42 aggregation, which is mitigated by native PLGA under in vitro conditions, providing a rationale to study it further under an in vivo paradigm to examine its significance in AD pathogenesis.},
}

*Amyloid beta-Peptides/metabolism/chemistry
*tau Proteins/metabolism/chemistry
*Alzheimer Disease/metabolism/pathology
*Nanoparticles/chemistry
*Peptide Fragments/metabolism/chemistry
*Polylactic Acid-Polyglycolic Acid Copolymer/chemistry
Humans
Protein Aggregates/drug effects
Animals
*Protein Aggregation, Pathological/metabolism

@article {pmid42794615,
year = {2026},
author = {Hedström, AK},
title = {Interpreting Viral Associations in Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
doi = {10.3390/ijms27188185},
pmid = {42794615},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/virology ; Animals ; *Virus Diseases/complications/virology ; Parkinson Disease/virology ; Amyotrophic Lateral Sclerosis/virology ; Herpesvirus 4, Human ; },
abstract = {Viral infections have been associated with multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), but the associations may reflect different relationships to the disease process. This review evaluates evidence for viral involvement in disease initiation, modification of established disease, impaired viral control secondary to disease or treatment, and incidental detection. The strongest temporal evidence concerns Epstein-Barr virus (EBV) and MS. Prospective data place EBV seroconversion before clinical onset and the first observed increase in serum neurofilament light chain, while mechanistic studies link EBV infection, B-cell biology, and CNS-directed immunity. However, evidence that ongoing EBV activity modifies established MS remains limited. In AD, experimental studies support interactions between herpesviruses and AD-associated proteins, while the reduced incidence of all-cause dementia after herpes zoster vaccination suggests that viral or immunological pathways may be modifiable, without establishing that a specific herpesvirus initiates AD. Viral associations in PD rely mainly on epidemiological, experimental, and postmortem findings. Human pegivirus detection in a subset of PD brains remains a candidate association requiring independent confirmation and evidence of biological activity. Evidence in ALS is similarly limited. Enterovirus detection has been inconsistent, and altered human endogenous retrovirus K (HERV-K) expression in postmortem tissue does not establish an acquired viral infection. Stronger inference across these diseases will require longitudinal studies relating viral activity and antiviral immunity to subsequent disease-related changes, together with intervention studies that document the intended effect on the implicated viral process and separately assess subsequent disease risk or progression.},
}

Humans
*Neurodegenerative Diseases/virology
Animals
*Virus Diseases/complications/virology
Parkinson Disease/virology
Amyotrophic Lateral Sclerosis/virology
Herpesvirus 4, Human

@article {pmid42778072,
year = {2026},
author = {Li, Y and Xue, X and Luo, H and Chen, D and Yang, S and Huang, X and Li, Y},
title = {Investigating the therapeutic mechanism of leech in vascular dementia: An integrated approach combining network pharmacology and experimental validation.},
journal = {Brain research bulletin},
volume = {245},
number = {},
pages = {112131},
doi = {10.1016/j.brainresbull.2026.112131},
pmid = {42778072},
issn = {1873-2747},
abstract = {BACKGROUND: Vascular dementia (VaD), the second leading cause of dementia following Alzheimer's disease, results from the reduction in cerebral blood flow. Medicinal leeches (SZ) in traditional Chinese medicine (TCM), a classic remedy for promoting blood circulation and improving blood stasis, have shown capabilities to relieve neuroinflammation and repair the blood-brain barrier (BBB) integrity. However, the efficacy and the underlying mechanisms of medicinal leeches in treating VaD remain unclear.

OBJECTIVE: This study aimed to explore the efficacy of medicinal leeches in treating VaD and its molecular mechanisms.

METHODS: An in vivo VaD model of rats was created via a two-vessel occlusion (2VO) ischemia protocol. Learning and memory functions in rats were assessed via the water maze test, Y-maze test, and novel object recognition test. The neuronal injury in rat hippocampus was assessed by H&E and Nissl staining. Network pharmacology (NP) and molecular docking depicted a "SZ-Compounds-Targets" network and visualized the binding pattern between core components of medicinal leeches and key targets of VaD, respectively. Transmission electron microscopy (TEM), ELISA, quantitative PCR, and Western blotting were performed to validate the involvement of the TLR4/NF-κB signaling pathway in leech treatment against VaD.

RESULTS: Medicinal leeches alleviated the cognitive deficits and neuronal injuries in VaD rats. Seven key targets were predicted as the leading contributors to the neuroprotective potential of medicinal leeches against VaD. Enrichment analyses further showed that the Toll-like receptor and NF-κB signaling pathways were enriched in the key targets of medicinal leeches. Experimental assays showed that expression levels of TLR4, MyD88, p-p65, and pro-inflammatory mediators were significantly elevated in VaD rats, which were further enhanced by LPS induction. Encouragingly, leech treatment significantly downregulated their levels.

CONCLUSION: Medicinal leeches can effectively alleviate the learning and cognitive impairments, neurological pathology in the hippocampal CA1 region, and the loss of BBB integrity in VaD rats. Moreover, medicinal leeches can suppress the neuroinflammation in VaD rats through inhibiting the TLR4/NF-κB signaling pathway.},
}

@article {pmid42778217,
year = {2026},
author = {Shinagawa, S and Nagata, T},
title = {Patient-Specific Clinical Formulation for Agitation in Alzheimer's Disease: Beyond Group-Level Evidence.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {e70220},
doi = {10.1111/psyg.70220},
pmid = {42778217},
issn = {1479-8301},
support = {24K10690//JSPS KAKENHI/ ; },
mesh = {Humans ; *Alzheimer Disease/complications/psychology/therapy ; *Psychomotor Agitation/therapy/etiology/drug therapy/psychology ; Japan ; *Antipsychotic Agents/therapeutic use ; },
abstract = {Agitation in Alzheimer's disease (AD) is clinically heterogeneous. Patients who meet the same syndromic definition can differ in the behaviour of greatest concern, the factors that precipitate or sustain it, the risks involved and their response to treatment. Randomised trials are essential for estimating average treatment effects; individual treatment selection also requires patient-specific clinical information. This review considers patient-specific clinical formulation as a practical way to connect group-level evidence with individual treatment decisions. The formulation makes explicit what is being treated, which contributors are plausible, which contextual or reversible factors matter, what outcome would count as meaningful improvement and when treatment should be changed or stopped. Treatment response then becomes additional clinical information: early benefit, adverse effects or an unexpected course may support or call into question the initial formulation. Non-pharmacological care and treatment of reversible causes remain the foundation of management, with medication reserved for agitation that is severe, persistent, dangerous or highly distressing. For Japan, we propose a formulation summary as a prototype for shared documentation across care settings; its feasibility and clinical value require prospective evaluation. Moving beyond group averages entails applying evidence more carefully to the needs of the individual patient.},
}

Humans
*Alzheimer Disease/complications/psychology/therapy
*Psychomotor Agitation/therapy/etiology/drug therapy/psychology
Japan
*Antipsychotic Agents/therapeutic use

@article {pmid42778344,
year = {2026},
author = {Tao, L and Liu, N and Zhang, W and Yang, Z and Xing, W and Wu, L and Hou, L and Wei, P and Xie, Y and Han, W and Liu, Y and Jin, Y and Xiang, L and Liu, X and Ma, W and Hu, P and Li, W and Zhou, W and Wang, S and Chen, H and Liu, P and Yin, D and Li, Y and Dooley, S and Zhang, L and Xu, J and Ji, G and Liu, C},
title = {Butyrylcholinesterase alleviates hepatic stellate cell activation via paracrine muscarinic signalling.},
journal = {Gut},
volume = {},
number = {},
pages = {},
doi = {10.1136/gutjnl-2026-338932},
pmid = {42778344},
issn = {1468-3288},
abstract = {BACKGROUND: Butyrylcholinesterase (BuChE) is a metabolic enzyme implicated in Alzheimer's disease, detoxification and depression. Although reduced BuChE expression is recognised in cirrhosis, its functional role in fibrogenesis remains undefined.

OBJECTIVE: We investigated whether BuChE regulates fibrosis by modulating acetylcholine (ACh) bioavailability and identified downstream cholinergic signalling.

DESIGN: BuChE expression was assessed via qPCR and immunostaining in patient biopsies. Its contribution was studied using Buche [ΔHep], Buche [KI/KI-Hep] mice, pharmacological inhibition, mutant BuChE conditioned medium and recombinant protein. ACh release and muscarinic ACh receptor (ChRM) function were measured using patch-clamp and calcium mobilisation assay; ChRM3 role was tested via Chrm3 [ΔHSC] mice and AAV6-mediated overexpression.

RESULTS: BUCHE mRNA and serum activity are significantly downregulated in fibrotic patients and mice, correlating negatively with F stage and alpha-smooth muscle actin expression. BuChE is predominantly expressed in hepatocytes in the liver, which can be reduced by transforming growth factor beta or platelet-derived growth factor treatment, and its anti-fibrotic function requires enzymatic activity. Hepatocyte BuChE deletion or inhibition increases hepatic stellate cell (HSC) activation and fibrosis across multiple models, whereas overexpression is protective, establishing causality. Loss of BuChE leads to accumulation of unmetabolised ACh, which activates HSCs as a damage associated molecular pattern signal via ChRM3-NF-κB signalling. Chrm3 [ΔHSC] mice exhibit attenuated HSC activation and fibrosis, whereas Chrm3 overexpression promotes fibrogenesis.

CONCLUSION: Hepatocyte injury disrupts BuChE activity, causing local ACh accumulation and subsequent HSC activation via ChRM3 signalling. This newly identified cholinergic circuit drives fibrosis and represents a druggable target for therapeutic intervention.},
}

@article {pmid42779999,
year = {2026},
author = {Kaser, AN and Stricker, JL and Hughes, MA and Corriveau-Lecavalier, N and Boots, EA and Machulda, MM and Fields, JA and Jones, DT and McCarter, SJ and Botha, H and Coburn, RP and Bermudez, C and Neth, BJ and Graff-Radford, J and Ramanan, VK and Stricker, NH},
title = {Feasibility of remote self-administered cognitive assessment in an Alzheimer's disease treatment clinic.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.15.26362283},
pmid = {42779999},
abstract = {INTRODUCTION: Remote cognitive assessments offer an accessible, scalable way to support clinical characterization and longitudinal monitoring of cognition. This study evaluates the feasibility of implementing Mayo Test Drive (MTD), a remote, self-administered digital cognitive assessment, within a specialized clinic focused on eligibility assessments for anti-amyloid therapies for Alzheimer's disease (AD).

METHOD: Two-hundred and nine (N =209) patients (M age =71.2, 53% female) were evaluated through the Mayo Clinic Rochester Alzheimer's Disease Treatment Clinic (ADTC) and had the opportunity to complete MTD, either as a remote, patient-initiated session through a patient-facing healthcare portal or during an in-clinic neuropsychological evaluation.

RESULTS: Clinical diagnoses included 55.2% mild cognitive impairment (MCI), 31.0% mild dementia, and 11.6% moderate dementia, in addition to 2.2% cognitively unimpaired (CU), as determined by neurology consensus at a multidisciplinary case conference. Among those who initiated MTD (n =197/209), 97.5% completed a session (70.6% remotely, 26.9% in clinic). Completion rates were high across diagnostic groups and did not significantly differ by clinical severity (p =.12): CU (100%), MCI (99.1%), mild dementia (97.0%), and moderate dementia (89.5%). Remote completion rates overall were high (97.9%). Among completers, administration setting (remote vs. in-clinic) did not significantly differ by clinical stage, χ²(3)=2.37, p =.49. Reasons for non-initiation included not receiving or opening portal messages and other/unknown factors.

DISCUSSION: Remote digital cognitive assessment is feasible within the context of clinic eligibility evaluations for AD therapies. The high completion rates of MTD across clinical impairment levels in this setting support development of paths for broader use in cognitive characterization in AD care.},
}

@article {pmid42780868,
year = {2026},
author = {Johnson, JC and Kashyap, B and Gustafson, SK and O'Brien, M and Frey, WH and Svitak, AL and Hanson, LR},
title = {Safety and tolerability of intranasal insulin in Parkinson's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1875165},
pmid = {42780868},
issn = {1664-2295},
mesh = {Humans ; Administration, Intranasal ; Female ; Male ; Aged ; *Insulin/administration & dosage/adverse effects ; *Parkinson Disease/drug therapy ; Double-Blind Method ; Middle Aged ; Aged, 80 and over ; *Hypoglycemic Agents/administration & dosage/adverse effects ; Adult ; },
abstract = {BACKGROUND: Repurposing therapeutic treatments for diabetes may be a promising strategy for the treatment of neurodegenerative disorders. Intranasal insulin (INI) is shown to improve memory, attention, and cognition in Alzheimer's dementia. Associations between the etiology of Parkinson's Disease (PD), brain glucose hypometabolism, and central insulin resistance suggest INI as a promising treatment for PD.

METHODS: A phase II single center, randomized, double-blind clinical trial was conducted in 30 participants with PD, aged 41-89, MoCA ≥ 16, on a stable dose of anti-PD medications. Participants were randomized to receive intranasal treatment for 21 days with either placebo, or 20, 40, or 80 IU of regular insulin (INI) using SipNose intranasal device. Primary outcomes of safety and tolerability were assessed in 30 participants by monitoring hypoglycemia, weight, and adverse events. Cognitive, mood, and motor measures were collected pre- and post-treatment for secondary outcome analysis and assessed in 28 participants.

RESULTS: No significant changes in weight or serum insulin were observed during the study. No hypoglycemic values (<70 mg/dL) were recorded 15 or 30 min post-IN dose. Nasal irritation and nosebleeds were the most common adverse events, with most categorized as "mild." Several secondary outcomes (e.g., verbal fluency and recall) improved from baseline in the 40 IU/INI arm only, though not significantly more than in the placebo arm. No other outcomes assessed (mood, apathy, motor) improved under INI treatment.

CONCLUSION: INI exhibits an acceptable safety profile in patients with PD. Further studies to investigate if INI has a positive impact on cognitive and motor symptoms in PD are warranted.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04251585 Identifier, NCT04251585.},
}

Humans
Administration, Intranasal
Female
Male
Aged
*Insulin/administration & dosage/adverse effects
*Parkinson Disease/drug therapy
Double-Blind Method
Middle Aged
Aged, 80 and over
*Hypoglycemic Agents/administration & dosage/adverse effects
Adult

@article {pmid42782577,
year = {2026},
author = {Salardini, A and Azarbar, S},
title = {Cognition in Cardiovascular Disease.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {42782577},
issn = {1534-6293},
mesh = {Humans ; *Cardiovascular Diseases/complications/pathology/psychology ; *Cognition Disorders/etiology ; *Cognition/physiology ; Brain/pathology ; Animals ; },
abstract = {PURPOSE OF REVIEW: Acute cerebrovascular events once dominated efforts to protect the brain from cardiovascular disease. As stroke prevention and treatment have advanced, attention has broadened to the more continuous vascular processes that contribute to cognitive decline across later life. This review organizes cardiovascular brain injury by route, direct structural injury versus indirect mediated pathways, and tempo, acute events versus chronic processes, with vessel caliber determining lesion topography.

RECENT FINDINGS: Vascular and Alzheimer pathology commonly coexist in older adults with cognitive impairment, and their relationship appears bidirectional but asymmetric: Alzheimer pathology can directly injure the cerebral vasculature, while vascular dysfunction may facilitate Alzheimer pathology and, more clearly, accumulated vascular injury lowers the threshold at which Alzheimer pathology becomes clinically expressed. Covert infarction, microbleeds, white matter disease, and blood-brain barrier disruption accumulate into a cumulative vascular substrate that erodes cognition over decades without requiring a recognized clinical event, and the clinical syndrome follows the lesion, with the subcortical dysexecutive phenotype the modal presentation. Evidence from SPRINT MIND, FINGER, US POINTER, BRAIN-AF, LACI-2, CREST-2, and Mendelian randomization identifies blood pressure control as the best-established intervention, uses discordant and null findings to refine presumed mechanisms, and frames the emerging dilemma of anti-amyloid therapy in patients with substantial vascular disease. In the mixed vascular and Alzheimer disease that dominates late-life dementia, the vascular component is often the more modifiable, and cardiovascular risk management remains among the most actionable strategies for preserving cognition.},
}

Humans
*Cardiovascular Diseases/complications/pathology/psychology
*Cognition Disorders/etiology
*Cognition/physiology
Brain/pathology
Animals

@article {pmid42783767,
year = {2026},
author = {Kang, Z and Meng, R and Nie, M and Wang, T},
title = {Gut Microbial Metabolism as a Dynamic Interface in Neurodegenerative Diseases.},
journal = {Metabolites},
volume = {16},
number = {9},
pages = {},
doi = {10.3390/metabo16090642},
pmid = {42783767},
issn = {2218-1989},
support = {No.82405557//China National Natural Science Foundation of youth project/ ; KM202410025018//R&D Program of Beijing Municipal Education Commission 2024: Study on the improvement of clinical symptoms and mechanism of acupuncture in amyotrophic lateral sclerosis/ ; 20250639//Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan/ ; 2024-QNRC2-B08//2024-2026 Chinese Association of Chinese Medicine young Talent lifting project/ ; },
abstract = {Gut microbial metabolism links intestinal ecology with systemic physiology and neural pathology, but its effects vary across disease stage, tissue compartment, and host background. This review uses Alzheimer's disease (AD) as the principal model and compares selected features with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Across the AD continuum, fermentation-related changes appear in prodromal cohorts, whereas broader alterations in amino acid products, host-microbial co-metabolites, bile acids, and lipids accompany mild cognitive impairment and dementia. These group-level patterns do not constitute a fixed patient trajectory. Microbial production, intestinal absorption, hepatic conversion, renal clearance, barrier integrity, and tissue-specific receptors jointly determine biological exposure. Experimental studies connect short-chain fatty acids and indole derivatives with epithelial and neuroimmune homeostasis, while imidazole propionate, trimethylamine N-oxide, selected kynurenine products, and remodeled bile acid pools engage vascular, inflammatory, amyloid, or tau-related pathways. Cerebral pathology can also remodel the intestinal ecosystem, creating reciprocal feedback. Apolipoprotein E4 modifies lipid handling, vascular permeability, and immune responses, helping to explain why comparable metabolic profiles may carry different consequences among individuals. Translation therefore requires more than a change in community composition. Trials must verify microbial function, metabolite target engagement, AD biomarker response, and clinical benefit in appropriately stratified participants. Shared pathways in PD and ALS provide comparison points, but disease-specific cells, proteinopathies, and treatment exposures constrain direct transfer of AD-derived targets.},
}

@article {pmid42769555,
year = {2026},
author = {Huang, L and Cheng, P and Liu, G and Xiang, Y and Hong, Z and Le, W},
title = {Myelin Impairment and Regeneration in the Central Nervous System: Molecular Mechanisms, Diseases, and Prospective Therapeutic Targets.},
journal = {MedComm},
volume = {7},
number = {10},
pages = {e71017},
pmid = {42769555},
issn = {2688-2663},
abstract = {Myelin plasticity is fundamental to the formation of neural networks and the optimization of neural functions, shaping circuits governing emotion, cognition, sensation, and motor control. Synthesized by oligodendrocytes, myelin undergoes lifelong remodeling that demands high metabolic activity; this renders the myelin-oligodendrocyte unit highly susceptible to metabolic stress, aging, and pathological insults. While demyelination is the core hallmark of various chronic neurological disorders, this review specifically highlights its emerging role in Alzheimer's disease (AD). Myelin impairment is increasingly recognized as an early pathological event in AD, potentially preceding the classic accumulation of amyloid plaques and neurofibrillary tangles. Here, we provide a comprehensive overview of myelin structure and function, evaluating the potential of tracking myelin changes as early diagnostic biomarker for AD. We further synthesize recent evidence regarding myelin pathology across a spectrum of central nervous system disorders including multiple sclerosis, leukodystrophies, cerebral small vessel disease, psychiatric disorders, and traumatic injury, highlighting the underlying pathological mechanisms. Furthermore, we examine emerging therapeutic strategies, ranging from pharmacological interventions to noninvasive stimulation, aimed at restoring oligodendroglial function and promoting remyelination. Finally, we offer a forward-looking perspective on myelin regeneration research, emphasizing its critical potential as a novel therapeutic target for AD and other neurodegenerative conditions.},
}

@article {pmid42769797,
year = {2026},
author = {Patel, MM and Nguyen, MD and Pistone, ES and Chowdhury, A and Phan, MH and El Ayadi, A and Song, J and Erickson, M},
title = {Out of the Fire, Into the Fog: Association Between Early Mechanical Ventilation and Delirium in Hospitalized Burn Patients.},
journal = {Cureus},
volume = {18},
number = {8},
pages = {e114981},
pmid = {42769797},
issn = {2168-8184},
abstract = {Introduction Delirium is a common and clinically significant complication among hospitalized burn patients, associated with increased morbidity, mortality, and healthcare utilization. While multiple factors contribute to delirium risk, mechanical ventilation has been associated with delirium, although this relationship may reflect underlying illness severity and ICU-level treatment exposure. However, large-scale, multicenter administrative analyses comparing coded outcomes between mechanically ventilated and non-ventilated burn patients remain limited. Methods A retrospective cohort study was conducted using the TriNetX (TriNetX, LLC, Cambridge, Massachusetts, United States) database to identify adult hospitalized burn patients with International Classification of Diseases (ICD)-coded burns involving ≥20% total body surface area. Patients were stratified into two cohorts based on receipt of mechanical ventilation within five days of the index burn event. Exclusion criteria included age <18 years and diagnoses of dementia, Alzheimer's disease, substance use disorders, or other conditions associated with baseline cognitive impairment. Cohorts were propensity score matched for age, sex, race, ethnicity, ICD-coded burn extent history, hypertension, diabetes, ischemic heart disease, sepsis, inhalation injury, and respiratory disorders. Outcomes assessed within 30 days included administratively documented delirium, disorientation, mortality, anxiety disorders, depressive disorders, and acute stress-related disorders. Results There were 1,541 patients in each cohort after matching. Ventilated patients had higher rates of administratively documented delirium (risk ratio (RR): 2.16, 95% CI: 1.51-3.09, p<0.0001), mortality (RR: 5.06, 95% CI: 4.23-6.05, p<0.0001), anxiety disorders (RR: 1.88, 95% CI: 1.58-2.21, p<0.0001), disorientation (RR: 3.39, 95% CI: 2.27-5.06, p<0.0001), and acute stress-related disorders (RR: 1.77, 95% CI: 1.40-2.22, p<0.0001). Depressive disorders were not significantly different between cohorts (RR: 1.42, 95% CI: 0.85-2.39, p=0.19). Discussion Early mechanical ventilation was associated with higher rates of administratively documented delirium, mortality, anxiety disorders, disorientation, and acute stress-related disorders among adult hospitalized burn patients. However, these findings likely reflect both ICU-level treatment exposure and substantial residual confounding by underlying illness severity. Early mechanical ventilation may identify a high-risk subgroup that warrants structured neurocognitive monitoring, psychological screening, sedation-conscious care, and post-extubation support. Given the observational design and reliance on administrative coding, these findings should be interpreted as hypothesis-generating.},
}

@article {pmid42769842,
year = {2026},
author = {Hou, C and Gao, Y and Wang, H},
title = {Exercise timing as a potential temporal regulator of neurolymphatic physiology in neurodegenerative proteinopathies: a mechanistic framework.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1879617},
pmid = {42769842},
issn = {1662-4548},
abstract = {Although physical activity is consistently associated with lower risks of cognitive decline, dementia, and Parkinson's disease, most exercise research in neurodegeneration still defines exposure by dose-based variables such as duration, intensity, frequency, step count, and cardiorespiratory fitness. This framework is useful for public-health guidance but biologically incomplete for progressive proteinopathies, in which the temporal accumulation and dissemination of misfolded proteins are central to disease evolution. In this review, we propose a temporal intervention framework in which exercise timing is treated as a mechanistic variable that may influence neurodegenerative biology through glymphatic-meningeal lymphatic clearance, vascular pulsatility, circadian alignment, and sleep architecture. We focus on Alzheimer's disease and Parkinson's disease because tau and α-synuclein propagation are disease-relevant processes that may be most amenable to intervention during preclinical or prodromal stages. Morning exercise may act primarily through circadian entrainment, afternoon exercise through vascular-metabolic stimulation, appropriately timed evening or low-intensity activity through sleep-related pathways, and sedentary fragmentation through effects on daytime cerebrovascular dynamics and rest-activity rhythm stability. Although the glymphatic-meningeal lymphatic axis provides a plausible link between timed exercise and extracellular protein handling, current human evidence remains indirect and relies heavily on imaging surrogate markers. Future matched-dose trials should integrate accelerometry, sleep physiology, circadian measures, vascular assessments, neurolymphatic imaging, and disease-specific protein biomarkers, including tau PET, plasma p-tau217, and α-synuclein seed amplification assays. Timed exercise should therefore be viewed as a testable biological perturbation that may clarify whether movement timing influences protein propagation in early neurodegenerative disease, not as a proven disease-modifying treatment.},
}

@article {pmid42770363,
year = {2026},
author = {Chi, L and Xu, F and Dai, X and Li, Z and Li, J and Li, Z},
title = {Immunity and Inflammation in Alzheimer's Disease: A Narrative Review on Mechanisms and Therapeutic Prospects.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050493089260903062914},
pmid = {42770363},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) is an age-related neurodegenerative disorder of the Central Nervous System (CNS), characterized by amyloid-β (Aβ) deposition and Neurofibrillary Tangles (NFTs) caused by the hyperphosphorylation of tau protein. Neuroinflammation is an increasingly recognized feature of AD, playing a critical role in disrupting the immune microenvironment within the brain parenchyma. High levels of various inflammatory mediators have been documented in both AD patients and experimental AD models. Similarly, multiple immune cells have been found to accumulate in the brain parenchyma, the meninges, and the choroid plexus. Therefore, antiinflammatory therapies, including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and immune regulatory strategies hold promise as potential novel approaches for the prevention and treatment of AD. Currently, a variety of anti-inflammatory agents and immunotherapies have demonstrated efficacy in AD animal models, and several clinical trials of immunotherapeutic interventions have been completed or are underway. This review systematically summarizes the core pathophysiological mechanisms by which inflammatory and immune dysfunctions contribute to AD pathogenesis and explores potential therapeutic interventions targeting these mechanisms, thereby providing theoretical insights for clinical translational research on AD treatment.},
}

@article {pmid42770364,
year = {2026},
author = {Pluta, R and Ułamek-Kozioł, M},
title = {Vitamin C versus Alzheimer's Disease. Commentary on the Effect of Ascorbic Acid on the Transgenic Drosophila Expressing Human Aβ-42 in the Neurons.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050513704260903053055},
pmid = {42770364},
issn = {1875-5828},
abstract = {A recent article by Siddique et al. published in Current Alzheimer's Research suggests that vitamin C may have a neuroprotective effect in Alzheimer's disease, which inspired us to write this commentary. In this commentary, we focus on the effects of vitamin C treatment on amyloid in a transgenic Drosophila melanogaster model of Alzheimer's disease. It should be noted that some of the information presented in this article raises more questions than it answers. The article does not provide a clear answer to the question posed in the title. We note that the authors demonstrated, to a very limited extent, the ameliorative effects of vitamin C on oxidative stress, cholinergic function, improved behavior, and prolonged lifespan, yet their enthusiasm for the therapeutic potential of vitamin C in Alzheimer's disease has not faded. In conclusion, the work contains controversial and speculative statements; therefore, drawing far-reaching conclusions and applying vitamin C to Alzheimer's disease are not justified by the available evidence.},
}

@article {pmid42770365,
year = {2026},
author = {Mehra, A and Sharma, R and Mittal, A},
title = {Cholinesterase Inhibitors in Alzheimer's Disease: Medicinal Chemistry, Mechanistic Insights, and Emerging Multitarget Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273435274260907101735},
pmid = {42770365},
issn = {1996-3181},
abstract = {Alzheimer's disease (AD) is the leading neurodegenerative disorder in the world. Although several decades of research have focused on its multifactorial pathogenesis, treating it remains a great challenge. The approved treatment options include cholinesterase inhibitors (ChEIs), which are the most common symptomatic treatment choice. These drugs act by inhibiting acetylcholinesterase (AChE) and, in some cases, butyrylcholinesterase (BuChE), preventing the breakdown of acetylcholine and increasing cholinergic neurotransmission in the brain. This review provides a broad consideration of ChEIs, focusing on their bioactivity, biochemical action, clinical significance, and SAR trends. It provides a comparative analysis of all the major chemical classes of ChEIs, namely the carbamates and organophosphates, as well as multiple heterocyclic scaffolds, with particular assessment of BBB permeability, metabolic stability, and toxicity attributes. Recent advances in medicinal chemistry have led to a shift in interest toward multi-target-directed ligands (MTDLs) that are designed not only to inhibit ChEs but also to exert antioxidant, anti-inflammatory, anti-amyloid, and metalchelating activity. These can target multiple pathogenic mechanisms to achieve a better therapeutic effect and neuroprotection. This review is based on a robust literature search conducted between 2020 and 2025. The progress, limitations, and prospects of ChEIs in the treatment of AD are critically assessed in this work. It also underscores the need for rational drug design to develop multitargetdirected drugs that may have disease-modifying effects, to overcome the limitations of existing symptomatic cholinesterase-inhibitor monotherapy.},
}

@article {pmid42771693,
year = {2026},
author = {Tariot, PN and Citrome, L and Clevenger, CK and Jackson, WC and Montano, CB and Patel, A and Porsteinsson, AP and Sabbagh, M},
title = {Targeted Treatment of Agitation in Alzheimer's Dementia: Prioritizing Function and Safety Over Sedation and Other Serious Harms.},
journal = {The primary care companion for CNS disorders},
volume = {28},
number = {5},
pages = {},
doi = {10.4088/PCC.haadachi2603},
pmid = {42771693},
issn = {2155-7780},
mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; *Psychomotor Agitation/drug therapy/etiology/therapy ; Primary Health Care ; *Hypnotics and Sedatives/therapeutic use/adverse effects ; *Antipsychotic Agents/therapeutic use/adverse effects ; },
abstract = {Agitation is a common and clinically significant neuropsychiatric condition in Alzheimer's dementia. Clinicians across the spectrum of care settings frequently encounter agitation but often lack practical clinical guidance. In April 2026, a consensus panel of clinical experts reviewed the literature and developed guidance for managing agitation in Alzheimer's dementia. The panel emphasized the critical role of primary care in agitation management and discussed different treatment approaches for optimizing patient and caregiver outcomes. Treatment should prioritize reduction of patient and caregiver distress and preservation of function rather than mere sedation. Discussion of neurobiology focused on the evolving models of frontal-limbic imbalance as the key driver of agitation in progressing Alzheimer's disease and implications for pharmacologic selection. The panel reviewed evidence on safety and efficacy of pharmacologic agents commonly used in agitation management and concluded that efficacy and safety profiles should guide clinical decision-making. The panel recommended conducting a behavioral assessment using validated tools, ruling out reversible causes, and using nonpharmacologic interventions as the first-line approach prior to starting pharmacologic treatment. Finally, setting-specific considerations were discussed. These recommendations complement prior guidance with a primary-care clinical decision pathway that matches treatment to the neurobiology of agitation and to comparative safety profiles, and that extends to the assessment, documentation, and coding clinicians need at the point of care. The goal is to help clinicians select evidence-based interventions for agitation in Alzheimer's dementia that prioritize safety, alertness, functional engagement, and caregiver well-being while minimizing the serious harms that have historically accompanied off-label management in this population, including excess mortality, cerebrovascular events, cognitive impairment, falls, and sedation. Prim Care Companion CNS Disord 2026;28(5):haadachi2603.},
}

Humans
*Alzheimer Disease/complications/drug therapy
*Psychomotor Agitation/drug therapy/etiology/therapy
Primary Health Care
*Hypnotics and Sedatives/therapeutic use/adverse effects
*Antipsychotic Agents/therapeutic use/adverse effects

@article {pmid42772203,
year = {2026},
author = {Miceli, F and Soldovieri, MV and Barrese, V and Taglialatela, M},
title = {Kv7 channels as pharmacological targets for central nervous system diseases.},
journal = {Pharmacological reviews},
volume = {78},
number = {6},
pages = {100153},
doi = {10.1016/j.pharmr.2026.100153},
pmid = {42772203},
issn = {1521-0081},
abstract = {Neuronal Kv7 (also known as KCNQ) voltage-gated potassium channels are key regulators of membrane excitability, primarily through their contribution to the M-current, a slowly activating and noninactivating potassium conductance that stabilizes the resting membrane potential and limits repetitive firing. Given the central role of the M-current in regulating critical central nervous system functions, it is not surprising that Kv7 channel dysfunction contributes to the onset and progression of a wide range of neuropsychiatric disorders, and that Kv7 channels are primary targets for pharmacological intervention in all these conditions. In this review, we provide a comprehensive overview of the physiological roles of neuronal Kv7 subunits (Kv7.2-Kv7.5) with particular emphasis on their expression patterns during development and across distinct neuronal populations. We also discuss the complex regulatory mechanisms governing Kv7 channel expression, trafficking, and function, including modulation by intracellular signaling pathways and interacting proteins. Particular attention is devoted to the involvement of Kv7 channel dysfunction in epileptic encephalopathies, pain syndromes, and neuropsychiatric conditions, as well as neurodegenerative disorders such as Alzheimer and Parkinson disease, where altered neuronal excitability is a common pathogenic hallmark. Furthermore, we examine the evolving pharmacological landscape of Kv7 channel modulators, from first-generation openers such as retigabine to next-generation agents, repurposed drugs, natural products, and Kv7 modulators currently in clinical development, highlighting both their therapeutic promise and existing challenges. Collectively, available evidence identifies Kv7 channels as versatile and highly attractive pharmacological targets for the treatment of central nervous system disorders characterized by maladaptive changes in neuronal excitability. SIGNIFICANCE STATEMENT: Kv7 channels are central regulators of neuronal excitability and are increasingly recognized as key therapeutic targets in multiple central nervous system disorders. Advancing our understanding of their pathophysiological role may enable the development of more selective and effective treatments for diseases driven by maladaptive changes in neuronal excitability.},
}

@article {pmid42773087,
year = {2026},
author = {Ritchie, M and Hussen, K and Langford, O and Donohue, MC and Sano, M and Grill, JD and Aisen, P and Sperling, R and Raman, R},
title = {Research satisfaction among participants in a preclinical Alzheimer's disease trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71852},
pmid = {42773087},
issn = {1552-5279},
support = {946223//American Heart Association/ ; U24AG053798//the NIA/ ; R01 AG063689/AG/NIA NIH HHS/United States ; U19AG010483/AG/NIA NIH HHS/United States ; U24AG057437/AG/NIA NIH HHS/United States ; //Eli Lilly/ ; //the Alzheimer's Association/ ; //the Accelerating Medicines Partnership/ ; //Foundation for the National Institutes of Health/ ; //Davis Alzheimer Prevention Program/ ; //Yugilbar Foundation/ ; //anonymous foundation/ ; //GHR Foundation/ ; //Additional private donors to Brigham and Women's Hospital, with in-kind support from Avid Radiopharmaceuticals, Cogstate, Albert Einstein College of Medicine and the Foundation for Neurologic Diseases/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Female ; Male ; Aged ; Surveys and Questionnaires ; *Patient Satisfaction ; Motivation ; },
abstract = {INTRODUCTION: Empirical data capturing participants' experiences in preclinical Alzheimer's disease (AD) trials are limited. We examined participant responses on a Research Satisfaction Survey (RSS) from the Anti-Amyloid Treatment in Asymptomatic AD Study.

METHODS: Participants completed the RSS at week 0, 48, 108, 168, and 240. We examined potential differences in responses by baseline participant characteristics and trial completion status.

RESULTS: RSS scores were high, with > 90% of participants responding positively to all satisfaction items. Across timepoints, altruistic motivations were most frequently affirmed, while study design elements were most frequently disfavored. Affirmation of social motivations increased over time. Participants who responded "not satisfied" at baseline to repeating their decision to enroll had higher odds of study discontinuation than those who responded "satisfied" (1.99; 95% confidence interval [CI]:1.24, 3.19).

DISCUSSION: An RSS captures participant experiences in a preclinical AD trial, can guide decisions on study design features, and may identify those at risk for loss to follow-up.},
}

Humans
*Alzheimer Disease/drug therapy/psychology
Female
Male
Aged
Surveys and Questionnaires
*Patient Satisfaction
Motivation

@article {pmid42774120,
year = {2026},
author = {Gong, C},
title = {Implications of pentose phosphate metabolism and astrocyte co-expression patterns in the pathogenesis of Alzheimer's disease: evidence from artificial intelligence-driven omics and clinical validation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1887060},
pmid = {42774120},
issn = {1662-4548},
abstract = {BACKGROUND: Metabolic reprogramming in glial cells is increasingly recognized as a pivotal factor in the pathogenesis of AD. While both the pentose phosphate pathway (PPP), a crucial metabolic route for redox balance and biosynthesis, and astrocyte reactivity are implicated in AD, their integrated molecular interaction between processes remains largely uncharted.

METHODS: We employed an integrated multi-omics and artificial intelligence (AI) framework. First, we applied the Limma, WGCNA, and xCell algorithms to bulk RNA-seq profiles from the hippocampus of AD patients to identify a gene signature linking the PPP and astrocyte reactivity (PA). This signature was then used to construct a diagnostic model via an explainable machine learning pipeline and to stratify patients into molecular subtypes through consensus clustering. The central hub gene of this PA-associated signature was subsequently validated using spatially and temporally resolved single-cell data from the AD hippocampus. An AI-based drug-repurposing screen (Drugreflector) and molecular docking simulations were used to identify natural compounds targeting this hub gene for the treatment of AD. Finally, the dysregulation of this target was confirmed by quantifying its expression in peripheral blood samples from a clinical AD cohort.

RESULTS: We identified eight PA-associated gene signatures in AD patients that can help elucidate the pathogenesis and molecular stratification. HDAC3 was identified as the central pathogenic hub, mainly distributed in astrocytes. Through drug screening, nervonic acid was identified as a potential therapeutic agent, showing a high binding affinity to HDAC3. Clinical validation confirmed elevated HDAC3 levels in AD patients.

CONCLUSION: Our study reveals a novel PA-associated molecular axis in AD, with HDAC3 serving as a central epigenetic-metabolic regulator within astrocytes. This co-expression axis provides a framework for patient subtyping, offers a promising diagnostic biomarker, and identifies a potential therapeutic target for AD.},
}

@article {pmid42775668,
year = {2026},
author = {Yin, Y and Li, Z},
title = {Mitochondrial Fusion and Fission in Age-Related Cardio-Cerebral Diseases: Mechanisms and Interventions.},
journal = {Aging cell},
volume = {25},
number = {10},
pages = {e70729},
pmid = {42775668},
issn = {1474-9726},
support = {2023JH2/101700204//The Science and Technology Program Joint Program of Liaoning Province (Project of Fundamental Research for Application)/ ; },
mesh = {Humans ; *Mitochondrial Dynamics/drug effects ; *Aging/metabolism/pathology ; Animals ; *Cardiovascular Diseases/metabolism/pathology ; *Cerebrovascular Disorders/metabolism/pathology ; *Mitochondria/metabolism ; },
abstract = {Mitochondria play a crucial role in cellular energy metabolism. The heart and brain require a continuous and stable energy supply. Energy production strongly depends on proper mitochondrial function. Mitochondrial fusion and fission, known as "plasticity", are vital for maintaining the normal physiological function of cells. Recent studies have shown that impaired mitochondrial dynamics are present in many aging-related diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and atherosclerotic cardio-cerebrovascular disease. The role of impaired mitochondrial dynamics in the pathophysiological process of aging-related diseases is being actively researched. We discovered that targeting proteins related to mitochondrial dynamics, especially those involved in fission and fusion, may offer new treatment strategies for these diseases. Various approaches, including aerobic interval and treadmill training and the use of drugs such as the antidiabetic agents metformin and dapagliflozin, the antihypertensive agent irbesartan, and certain traditional Chinese medicine components, have shown potential in alleviating imbalances in mitochondrial dynamics in aging-related cardio-cerebrovascular diseases. In this review, we systematically summarize recent research on alterations in mitochondrial dynamics in age-related cardio-cerebral diseases and explore therapeutic strategies targeting these alterations, which may offer new directions for improving cardiac and brain health and guiding clinical practice.},
}

Humans
*Mitochondrial Dynamics/drug effects
*Aging/metabolism/pathology
Animals
*Cardiovascular Diseases/metabolism/pathology
*Cerebrovascular Disorders/metabolism/pathology
*Mitochondria/metabolism

@article {pmid42777020,
year = {2026},
author = {Wang, D and Yan, S and Zhou, R and Li, Y and Liu, L and Wei, Y and Wang, D and Yao, H and Zhou, B and Lu, J and Wang, P and Liao, Z and Chen, Y and Zhang, X and Han, Y and Yu, C and Zhao, K and Liu, Y and , },
title = {Beyond statistical thresholds: Mapping sequential ATN cascade transitions via brain structural topography in Alzheimer's disease.},
journal = {Science advances},
volume = {12},
number = {39},
pages = {eaef3787},
pmid = {42777020},
issn = {2375-2548},
mesh = {*Alzheimer Disease/metabolism/pathology/diagnostic imaging ; Humans ; *Brain/pathology/metabolism/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Proteomics/methods ; Neuroimaging/methods ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease is widely conceptualized as a biological continuum initiated by amyloid-β (Aβ) accumulation, followed by tau aggregation and neurodegeneration. Although the ATN framework is commonly used to define disease stages, its static biomarker categories may not fully capture the dynamic pathological transitions that determine the optimal window for anti-Aβ therapies. Here, we introduce a Biological Continuum framework that distinguishes dynamic pathological cascades from static biomarker categories. Using neuroimaging-derived brain network topology, we identify four reproducible subgroups that exhibit distinct biological processes, biomarker signatures, and longitudinal cognitive trajectories. Integrated proteomic analyses suggest that these subgroups reflect sequential molecular transitions corresponding to early vulnerability, initiation, amplification, and terminal stages. Post hoc analysis indicates that slower cognitive decline after amyloid-targeting treatment was observed mainly in the initiation stage group. These findings provide a biologically grounded stratification system that captures disease dynamics overlooked by threshold-based models and offers mechanistic insight into the timing of anti-Aβ therapies.},
}

*Alzheimer Disease/metabolism/pathology/diagnostic imaging
Humans
*Brain/pathology/metabolism/diagnostic imaging
Amyloid beta-Peptides/metabolism
Biomarkers/metabolism
Proteomics/methods
Neuroimaging/methods
tau Proteins/metabolism

@article {pmid42777389,
year = {2026},
author = {Imbimbo, BP and Pomara, N and Pini, L and Frederiksen, KS},
title = {Repeated clinical trial failures in Alzheimer's disease: The pitfalls of pursuing epidemiological associations.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {204},
number = {},
pages = {119943},
doi = {10.1016/j.biopha.2026.119943},
pmid = {42777389},
issn = {1950-6007},
abstract = {Interventions for Alzheimer's disease (AD) have repeatedly been advanced from epidemiological associations, biological hypotheses and preclinical findings, yet many have failed in randomized trials and some have produced signals of clinical worsening. We examine illustrative successful and unsuccessful programs across infectious, inflammatory, metabolic, lipid, iron, dietary, hormonal and amyloid domains to determine what they reveal about causality and therapeutic translation. Negative results may indicate a non-causal or poorly specified target, but may also reflect inadequate central nervous system exposure, target engagement, disease-stage alignment, biomarker selection, population representativeness, statistical power, outcome selection or trial design. More informative programs distinguish prevention from symptomatic treatment, confirm AD pathology, establish central exposure and interpret target engagement together with clinical and functional outcomes rather than treating biomarker movement as a surrogate for benefit. We propose a causal-validation framework integrating convergent human evidence, mechanistic direction, central target engagement, supportive downstream biology, stage-appropriate and inclusively validated populations, and adequate design and power. Applying this framework before phase 3 testing should improve target selection, sharpen interpretation of negative trials and reduce costly late-stage failure.},
}

@article {pmid42761709,
year = {2026},
author = {Shahzad, M and Mushtaq, A and Rochais, C and Naseer, MM},
title = {Isatin derivatives as potent cholinesterase inhibitors: recent developments and future challenges.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42761709},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and neuronal loss, primarily associated with β-amyloid plaque deposition, tau hyperphosphorylation, and cholinergic dysfunction. Since the disruption of cholinergic neurotransmission is a key pathological feature of AD, the cholinesterase (ChE) inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) remain the mainstay of symptomatic treatment by enhancing synaptic acetylcholine levels. However, the currently approved small molecules, including tacrine, donepezil, rivastigmine, and galantamine, are limited by their modest efficacy, poor selectivity, and adverse effects, necessitating the development of improved therapeutic agents. Among emerging scaffolds, isatin (1H-indole-2,3-dione) has attracted considerable research attention owing to its structural versatility, synthetic accessibility, and favorable pharmacological properties. Recent studies have reported diverse isatin-based derivatives, including hydrazones, Schiff bases, thiosemicarbazones, spirooxindoles, and molecular hybrids, exhibiting potent AChE and BChE inhibitory activities, often in the submicromolar or nanomolar ranges. Structure-activity relationship studies have revealed the critical influence of electronic effects, linker optimization, N-substitution, and molecular hybridization on inhibitory potency and selectivity. This review summarizes the most promising isatin-based cholinesterase inhibitors reported from 2020 to the present, highlighting their biological activities, structure-activity relationships, and potential for the development of next-generation anti-Alzheimer therapeutics.},
}

@article {pmid42763072,
year = {2026},
author = {Shehu, K and Onimisi, OB and Bunza, HA and Umar, SM and Oyem, JC and Adewumi, TA},
title = {Prenatal origins of neurodegeneration: The role of maternal immune activation in Alzheimer's and Parkinson's pathobiology.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {116029},
doi = {10.1016/j.expneurol.2026.116029},
pmid = {42763072},
issn = {1090-2430},
abstract = {Recent evidence suggests that prenatal environmental factors, particularly maternal infection or maternal immune activation (MIA), may influence the progression of brain aging and lifetime risk for neurodegenerative disorders. The hypothesis is that even a short-lived inflammatory event during pregnancy may leave a lasting imprint on the developing brain and immune system of the fetus, such that aging or subsequent insults may later unmask neurodegenerative disorders. Support for this hypothesis comes largely from animal studies, where gestational inflammation has been shown to potentiate the onset of Alzheimer's and Parkinson's diseases (AD/PD), by increasing amyloid/tau pathology, reducing synaptic connections, and damaging nigrostriatal dopaminergic neurons. We review convergent mechanisms, including microglial priming, chronic cytokine excess, oxidative stress, epigenetic marks and proteostatic deficits, through which maternal immune activation may embed a latent "hit" that synergizes with aging to precipitate AD or PD. Furthermore, we appraise experimental models and available human data linking MIA to AD versus PD, noting shared and distinct pathways. Despite growing preclinical evidence, translation to human cohorts remains limited by heterogeneity in MIA exposure timing and outcome measures. An understanding of MIA's impact on neurodegeneration could suggest preventive strategies and interventions for early diagnosis and treatment.},
}

@article {pmid42763350,
year = {2026},
author = {Duan, X and Chen, Z and Tong, X and Li, X and Liu, Z and Yang, Y and Liu, X and Liu, W},
title = {Irisin-BDNF axis mediates muscle-brain communication: a complete molecular cascade and potential bidirectional feedback from peripheral activation to central protection.},
journal = {Biogerontology},
volume = {27},
number = {5},
pages = {},
pmid = {42763350},
issn = {1573-6768},
support = {Grant No. 2026JJ90271//Natural Science Foundation of Hunan Province/ ; },
mesh = {Humans ; *Brain-Derived Neurotrophic Factor/metabolism ; *Fibronectins/metabolism ; Animals ; *Brain/metabolism ; *Muscle, Skeletal/metabolism ; *Alzheimer Disease/metabolism ; Myokines ; Signal Transduction ; Feedback, Physiological ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline, with core pathological mechanisms including β-amyloid (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, and impaired synaptic plasticity. Although exercise has neuroprotective effects, the molecular mechanisms by which it mediates peripheral-central communication remain unclear. The concept of the 'muscle-brain dialogue' offers a new perspective on this process. irisin, secreted by skeletal muscle in response to exercise, forms a molecular link between peripheral exercise and central neuroprotection by specifically regulating brain-derived neurotrophic factor (BDNF). This review summarizes the molecular cascade mechanisms of the irisin-BDNF axis in mediating the muscle-brain dialogue: Irisin is synthesized via the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)/fibronectin domain-containing protein 5 (FNDC5) pathway. Current evidence suggests that peripheral irisin may communicate with the central nervous system through mechanisms related to the blood-brain barrier, including potential αVβ5 integrin-mediated interactions, thereby participating in the regulation of BDNF. As a core effector molecule, BDNF improves cognitive decline in AD by enhancing neuroplasticity, reducing Aβ deposition, inhibiting tau hyperphosphorylation, and alleviating neuroinflammation. However, oxidative stress and mitochondrial dysfunction associated with AD pathology negatively regulate this axis, creating a vicious cycle. Therefore, this paper explores potential intervention strategies and the prospects for future translational research, including upstream exercise interventions, midstream barrier-crossing enhancing peptides, and downstream small-molecule TrkB agonists. Targeting this axis provides a new theoretical foundation and translational direction for the early prevention and treatment of AD, as well as for drug development.},
}

Humans
*Brain-Derived Neurotrophic Factor/metabolism
*Fibronectins/metabolism
Animals
*Brain/metabolism
*Muscle, Skeletal/metabolism
*Alzheimer Disease/metabolism
Myokines
Signal Transduction
Feedback, Physiological

@article {pmid42763962,
year = {2026},
author = {Ye, J and Yin, S and Lin, Y and Yang, S and Ma, L and Wang, Y and Gao, K and Wang, Y and Yang, X and Yang, Z and Wang, N and Liu, H and Xu, S and Cui, W and Zhang, B},
title = {Substituted methyl acridone-carboxylate derivatives as CD1/CD2 dual-targeting HDAC6 inhibitors to ameliorate the pathological phenotype of Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {320},
number = {},
pages = {119350},
doi = {10.1016/j.ejmech.2026.119350},
pmid = {42763962},
issn = {1768-3254},
abstract = {Histone deacetylase 6 (HDAC6) has emerged as a promising target for Alzheimer' disease (AD). Although most reported HDAC6 inhibitors were designed to target CD2 catalytic domain, recent studies highlighted the functional importance of CD1 domain for the regulation of AD-related substrates. In this study, a series of substituted methyl acridone-carboxylate derivatives bearing a methyl ester moiety were discovered as CD1/CD2 dual-targeting HDAC6 inhibitors. The leading compound 6c could direct bind to HDAC6, and selectively inhibits HDAC6 with a high affinity in vitro. Molecular docking analysis revealed that 6c forms non-chelating coordination interactions with the zinc ions in both CD1 and CD2 domains of HDAC6. 6c inhibited Aβ oligomer-induced microtubule depolymerization and microglial phagocytic impairments in vitro. Furthermore, 6c effectively prevented HDAC6-driven α-tubulin and Hsp90 deacylation, as well as cognitive impairments in Aβ1-42 oligomer-treated mice. Combined with the acceptable physicochemical properties and promising biosafety of 6c, this study suggested that substituted methyl acridone-carboxylate derivatives, as CD1/CD2 dual-targeting HDAC6 inhibitors, might be developed as a novel lead drug for the treatment of AD.},
}

@article {pmid42764767,
year = {2026},
author = {Wenxin, S and Youmao, Z and Wenhua, H},
title = {Basic Research on the Lymphatic System and Exploratory Research in LVA Surgery for Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050503391260907045733},
pmid = {42764767},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive decline. Its characteristic pathological features include Aβ plaque deposition and abnormal tau protein aggregation. Biomarker testing has improved AD diagnosis. However, current treatments are primarily symptomatic, and no effective therapies are available to slow disease progression.

MATERIALS AND METHODS: In this review, PubMed, CNKI, Wanfang Data, and the Chinese Medical Journal Full-text Database were searched using core terms including lymphatic system, Alzheimer's disease, and deep cervical lymphatic-venous anastomosis with supplementary synonyms. After deduplication and two-round screening, irrelevant, duplicate, low-quality, and non-full-text articles were excluded, and eligible literature was systematically summarized.

RESULTS: The proposal of the glymphatic system has refined the theory of cerebral fluid circulation and waste clearance. Its dysfunction is closely associated with neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD), providing a novel target for AD treatment. Deep cervical Lymphatic-Venous Anastomosis (LVA), as an emerging surgical approach with potential to alleviate AD symptoms, has been initially validated for its short-term efficacy. However, it is still in the early stage of clinical exploration, and further systematic research is required for its successful clinical translation.

DISCUSSION: The glymphatic system mediates brain fluid circulation and waste clearance, providing new insights into AD pathogenesis and treatment. Building on this understanding, deep cervical Lymphatic-Venous Anastomosis (LVA) has emerged as a promising surgical intervention to alleviate AD pathology. Nevertheless, the considerable technical demands and incompletely elucidated mechanism of LVA severely limit its clinical translation, rendering these challenges a central research priority.

CONCLUSION: Breakthroughs in the central lymphatic system have provided an important direction for exploring the pathological mechanisms of AD and developing innovative therapeutic strategies. Clarifying the theoretical basis and technical evolution of LVA surgery, as well as addressing relevant controversial issues, constitutes a key focus to advance the basic research and clinical translation of AD treatment.},
}

@article {pmid42764861,
year = {2026},
author = {Qin, F and Zhang, N and Jiang, Y and Xu, K and Xiong, Y and Liu, Y and Ouyang, Q and Liu, H and Dai, Y and Jiang, L and Zhao, Y and Li, H and Wang, L and Chen, Y and Hu, L and Bu, Q and Zhao, Y and Kuang, W and Qin, M and Cen, X},
title = {Neutrophil-mediated BDNF delivery for the treatment of moderate to severe Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {9},
pages = {6185-6202},
pmid = {42764861},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD), especially its moderate-to-severe stage (MSAD), remains a global health challenge with no disease-modifying therapies. Here, we identified a dual pathological signature in MSAD patients and murine models: a systemic pro-inflammatory milieu and critically reduced brain-derived neurotrophic factor (BDNF) levels in both the hippocampus and serum. To mitigate the decrease in BDNF, we developed an engineered neutrophil capsule, in which neutrophils carrying lipid nanoparticles encapsulating BDNF penetrated the brain and ameliorated cognitive capacity deficits in MSAD mice. The pro-inflammatory state in the MSAD brain facilitated neutrophil passage through the blood-brain barrier, and inflammatory mediators triggered the release of BDNF from the engineered neutrophils. Collectively, our findings show that engineered neutrophil-mediated brain delivery of BDNF efficiently reduces the amyloid-β plaque deposition in the hippocampus, leading to significantly improved learning and memory in MSAD mice. This study establishes neutrophil-mediated delivery as a paradigm strategy for MSAD, merging cell biology with nanotechnology to reverse neurodegeneration.},
}

@article {pmid42767717,
year = {2026},
author = {Maiese, K},
title = {Running out the clock: Circadian rhythm dysfunction in cognitive disease.},
journal = {International review of neurobiology},
volume = {190},
number = {},
pages = {231-306},
pmid = {42767717},
issn = {2162-5514},
support = {R01 NS053946/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Animals ; *Chronobiology Disorders/metabolism/physiopathology ; *Circadian Rhythm/physiology ; *Cognitive Dysfunction/metabolism/physiopathology ; *Cognition Disorders/physiopathology/metabolism ; },
abstract = {Lifespan is increasing such that within a few decades approximately twenty percent of the world's population is expected to be greater than sixty years of age. In concert with global aging of the population, neurodegenerative disorders have become the leading cause of disability with dementia now the seventh leading cause of death worldwide. Despite multi-faceted treatment approaches for disorders of cognition that include Alzheimer's disease and multiple sclerosis, present therapies ultimately cannot halt disease progression and eventually cognitive impairment continues unabated. Furthermore, co-morbidities, such as metabolic disorders with diabetes mellitus, also lack strategies to prevent disease progression. Given these clinical challenges for cognitive loss, innovative avenues of investigation that involve mammalian chronobiology with circadian rhythm clock genes and related pathways of aging, cellular senescence, oxidative stress, metabolic dysfunction, sleep fragmentation, apolipoprotein E, programmed cell death, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), nicotinamide adenine dinucleotide, the gut microbiota, and glucagon-like peptide-1 receptor agonism may offer exceptional promise for forging new strategies for cognitive disease treatment. These pathways are intimately linked to circadian rhythm processes, are complex in generating biological outcomes, can broadly influence clinical translation of both short- and long-term considerations for cognitive disease care, and necessitate dissection of their precise regulatory mechanisms with the benefit from early diagnostic platforms as well as artificial intelligence and machine learning applications to foster translation of these pathways into effective clinical treatments.},
}

Humans
Animals
*Chronobiology Disorders/metabolism/physiopathology
*Circadian Rhythm/physiology
*Cognitive Dysfunction/metabolism/physiopathology
*Cognition Disorders/physiopathology/metabolism

@article {pmid42756207,
year = {2026},
author = {Panabakam, N and Elangovan, K and Seerangan, K and Manogaran, N and Malleeswaran, K and Yogarayan, S},
title = {Alzheimer's disease detection from structural brain MRI using FFA U-Net segmentation and transfer learning.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1871982},
pmid = {42756207},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to a gradual decline in cognitive and memory function. Multimodal neuroimaging, particularly magnetic resonance imaging (MRI), has become a central diagnostic tool for tracking disease progression, supporting diagnosis, treatment planning, and follow-up monitoring. Manual delineation of brain structures by clinicians remains time-consuming and labor-intensive, and computer-assisted segmentation is complicated by spatial and structural variability as well as intensity inhomogeneity across images. This study proposes an integrated framework for automated brain image segmentation and AD classification to address these challenges.

METHODS: The framework combines a modified U-Net architecture, termed FFA U-Net, with a fine-tuned VGG16 classifier. FFA U-Net incorporates a residual inception module and a feature fusion attention mechanism into the standard U-Net backbone to perform end-to-end brain tissue segmentation. Segmented outputs are subsequently passed to the fine-tuned VGG16 model for classification of AD status. The framework was evaluated on two datasets, ADNI (843 images) and OASIS (416 images), using subject-wise, non-overlapping training, validation, and test splits to prevent data leakage.

RESULTS: The proposed framework achieved a segmentation Dice Similarity Coefficient (DSC) of 0.929 and a classification accuracy of 98.90%, based on a single data split. These results were consistent across both the ADNI and OASIS datasets, indicating competitive segmentation and classification performance.

DISCUSSION: The findings suggest that combining attention-augmented segmentation with transfer learning-based classification can effectively support automated AD detection from structural MRI, potentially reducing the manual burden on clinicians. As results are based on a single split, further validation using cross-validation or independent cohorts is warranted to confirm robustness and generalizability. The framework should currently be regarded as an experimental research tool that requires additional clinical validation before deployment in practice.},
}

@article {pmid42756662,
year = {2026},
author = {Mirshekar, MA and Nadi, F and Fanaei, H and Chahkandi, M},
title = {Modulation of spatial learning and memory by cannabinoid-estrogen interaction in an AD-like cognitive impairment: The role of cannabinoid receptors and BDNF protein.},
journal = {IBRO neuroscience reports},
volume = {21},
number = {},
pages = {780-789},
pmid = {42756662},
issn = {2667-2421},
abstract = {Alzheimer's disease (AD) is an increasingly prevalent neurodegenerative disorder worldwide, with women showing a higher risk of developing the disease. The decline in steroid hormones after menopause may contribute to the increased susceptibility of women to neurodegenerative conditions. In parallel, cannabis-derived compounds have been reported to alleviate certain symptoms associated with neurological disorders. The present study was designed to investigate the effects of marijuana extract on cognitive impairment and hippocampal molecular markers in an ovariectomized AD-like rat model, and to evaluate whether co-administration with estradiol modifies these effects. The marijuana extract used in this study was characterized by HPLC and was found to contain 8.5% Δ9-THC. AD-like cognitive impairment pathology was induced by intra-hippocampal administration of Aβ25-35 in OVX rats. Animals were treated with marijuana extract (60 mg/kg/day, corresponding to approximately 5.1 mg/kg/day Δ9-THC) either alone or in combination with 17β-estradiol (1 mg/kg every 4 days) for 28 days. Cognitive performance was evaluated using the Morris water maze (MWM). In addition, hippocampal CB1/CB2 receptor expression and BDNF protein levels were measured to examine potential molecular associations. Our findings showed that chronic administration of the marijuana extract improved Aβ25-35-induced deficits in spatial learning and memory. Alterations in CB1 receptor expression and BDNF levels accompanied these behavioral effects. Notably, co-treatment with estradiol did not produce a synergistic effect, suggesting a complex interaction between cannabinoid-related and estrogen-related signaling pathways. These preclinical findings suggest that a THC-standardized marijuana extract may exert neuroprotective-like effects in an AD-like cognitive impairment model. However, because the extract was not fully phytochemically characterized and the mechanistic analyses were correlational, the results should be interpreted cautiously. Further studies are needed to clarify the underlying mechanisms and translational relevance of these findings.},
}

@article {pmid42756830,
year = {2026},
author = {Li, X and Miao, Z and Bi, J and Zhang, J and Wang, N},
title = {Sucralose Induces Neurobehavioral Alterations and Exacerbates Alzheimer's Disease-Like Phenotypes in Zebrafish Models.},
journal = {ACS omega},
volume = {11},
number = {36},
pages = {54169-54186},
pmid = {42756830},
issn = {2470-1343},
abstract = {Artificial sweeteners are widely consumed, yet their potential neurotoxic effects remain poorly understood. Using sucralose (SUC) as a model compound, this study develops an approach to rapidly screen the neurotoxicity of artificial sweeteners and explore their potential associations with neurodegenerative-like processes, especially Alzheimer's disease (AD)-like phenotypes. SUC is minimally absorbed and metabolized by mammals, leading to its widespread presence in the environment. Here, we integrate high-throughput behavioral phenotyping in larval zebrafish with targeted analyses in adult and AD transgenic models, employing a "behavioral phenoblast" strategy adapted from prior large-scale sleep-wake drug screens. SUC effects were evaluated across a broad concentration range (5 μg/L to 100 mg/L), covering low-dose to high-dose exposure conditions. Hierarchical and K-means clustering revealed that SUC's behavioral signatures closely resembled those of compounds associated with neurodegenerative risks. To validate these findings, adult zebrafish were exposed to SUC within the Acceptable Daily Intake (ADI) range (1-100 mg/L) for 3 months, resulting in dose-dependent increases in anxiety-like behaviors and impairments in learning and memory. Notably, treatment of transgenic zebrafish expressing human misfolded Aβ protein with SUC exacerbated Aβ-related pathological phenotypes in a dose-dependent manner. These findings highlight the need for further investigation into the long-term neurological impacts of artificial sweeteners and provide a methodological framework for evaluating the potential health risks of artificial sweeteners.},
}

@article {pmid42757822,
year = {2026},
author = {Gaber, DA},
title = {Engineering centrifugally spun nanofibrous matrices as high-performance transdermal patches for accelerated Alzheimer's treatment.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/09205063.2026.2734516},
pmid = {42757822},
issn = {1568-5624},
abstract = {This study aimed to develop and optimize a centrifugally spun polycaprolactone/poly(vinyl alcohol) (PCL/PVA) nanofibrous transdermal patch containing polyethylene glycol 400 (PEG 400) and oleic acid to improve rivastigmine delivery for the long-term management of Alzheimer's disease. Rivastigmine-loaded nanofibrous patches were fabricated by centrifugal spinning and characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). Mechanical properties, drug release, ex vivo skin permeation and deposition, dermal irritation, pharmacokinetics in New Zealand White rabbits, and stability were systematically evaluated. The optimized formulation (F5) produced uniform, bead-free nanofibers (1.7 ± 0.3 μm) with rivastigmine molecularly dispersed in an amorphous state within the polymeric matrix. The patch exhibited favorable mechanical properties, sustained drug release, enhanced ex vivo skin permeation (0.50 ± 0.04 mg/cm[2] at 24 h), and increased drug deposition within the viable epidermis and dermis, indicating cutaneous reservoir formation. Dermal irritation was negligible (Primary Irritation Index = 0.08). Pharmacokinetic studies demonstrated prolonged systemic absorption (Tmax = 6.0 ± 1.0 h) and approximately five-fold greater systemic exposure (AUC0-∞ = 345 ± 28 ng·h/mL) than the oral formulation (67 ± 9 ng·h/mL, p < 0.05).The optimized centrifugally spun nanofibrous patch provided sustained rivastigmine delivery, excellent dermal biocompatibility, enhanced skin deposition, and improved systemic bioavailability, supporting its potential as a scalable transdermal platform for long-term Alzheimer's disease therapy.},
}

@article {pmid42758107,
year = {2026},
author = {Abdanipour, A and Nikfar, A and Feizi, H},
title = {Selegiline induces neuroprotection via PGC-1α/Nrf2 gene upregulation in H2O2 -treated hippocampal-derived neural stem/progenitor cells.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {72},
number = {5},
pages = {47-53},
doi = {10.14715/cmb/2026.72.5.7},
pmid = {42758107},
issn = {1165-158X},
mesh = {*Selegiline/pharmacology ; *Hydrogen Peroxide/pharmacology/toxicity ; Animals ; *NF-E2-Related Factor 2/genetics/metabolism ; *Hippocampus/cytology ; *Neural Stem Cells/drug effects/metabolism/cytology ; *Up-Regulation/drug effects ; Apoptosis/drug effects ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; *Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; Oxidative Stress/drug effects ; Rats ; Cells, Cultured ; Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Neuroprotection/drug effects ; },
abstract = {Oxidative stress mediated by reactive oxygen species (ROS) is a major contributor to the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, and amyotrophic lateral sclerosis. Selegiline, a monoamine oxidase B inhibitor, has been reported to exert neuroprotective effects, although its precise cytoprotective mechanisms remain unclear. In this study, we investigated the effects of selegiline on apoptosis, necrosis, and cell survival in hydrogen peroxide (H2O2)-treated hippocampal-derived neural stem/progenitor cells (HD-NSPCs) in vitro. Passage 3 HD-NSPCs were treated with varying concentrations of selegiline (10[-3] to 10[-9] M) prior to exposure to 125 μM H2O2. Cell viability was assessed using the MTT assay, while apoptosis and necrosis were evaluated using TUNEL and acridine orange/ethidium bromide staining, respectively. Real-time RT-PCR was performed to quantify mRNA levels of PGC-1α, Nrf2, and Bcl-2. Treatment with 10[-7] M selegiline significantly enhanced HD-NSC viability, reduced apoptotic and necrotic cell fractions, and upregulated PGC-1α, Nrf2, and Bcl-2 expression compared to untreated cells (P < 0.05). These findings suggest that selegiline mitigates oxidative stress-induced cytotoxicity by activating Nrf2/PGC-1α signaling and promoting anti-apoptotic gene expression, thereby preserving mitochondrial function and enhancing cell survival. Overall, selegiline may represent a promising therapeutic agent for protecting neural progenitor cells and alleviating neuronal damage in neurodegenerative disorders.},
}

*Selegiline/pharmacology
*Hydrogen Peroxide/pharmacology/toxicity
Animals
*NF-E2-Related Factor 2/genetics/metabolism
*Hippocampus/cytology
*Neural Stem Cells/drug effects/metabolism/cytology
*Up-Regulation/drug effects
Apoptosis/drug effects
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism
*Neuroprotective Agents/pharmacology
Cell Survival/drug effects
Oxidative Stress/drug effects
Rats
Cells, Cultured
Proto-Oncogene Proteins c-bcl-2/metabolism/genetics
*Neuroprotection/drug effects

@article {pmid42758114,
year = {2026},
author = {Ran, J and Wei, Q and Lu, T and Liao, X and Pang, X and Zhu, Q and Zhou, H and He, X},
title = {Cognitive-enhancing effects of a herbal combination on D‑galactose‑induced memory impairment.},
journal = {Cellular and molecular biology (Noisy-le-Grand, France)},
volume = {72},
number = {5},
pages = {1-6},
doi = {10.14715/cmb/2026.72.5.1},
pmid = {42758114},
issn = {1165-158X},
mesh = {Animals ; *Galactose ; *Memory Disorders/drug therapy/chemically induced ; Cognitive Enhancement ; Acetylcholinesterase/metabolism ; Male ; Mice ; Cholinesterase Inhibitors/pharmacology/therapeutic use ; Maze Learning/drug effects ; Signal Transduction/drug effects ; Malondialdehyde/metabolism ; Hippocampus/drug effects/pathology/metabolism ; Oxidative Stress/drug effects ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, for which effective pharmacological interventions remain limited. This study investigated the cognitive-enhancing effects of an optimized six‑herbal combination (HC) comprising Polygonati Rhizoma (PR), Lycium barbarum polysaccharides (LBPs), Green Tea (GT), Jujube Seeds (JS), Fructus hippophae (FH), and Mori Folium (MF). Using the Ellman method, we evaluated the acetylcholinesterase (AChE) inhibitory activities of individual herbs and HC. An L25(4[6]) orthogonal design was employed to determine the optimal proportions of the six herbs, with AChE inhibition as the evaluation index. The optimal HC composition (PR 9 g, LBPs 6 g, GT 3 g, JS 3 g, FH 3 g, MF 5 g) exhibited 88.11% AChE inhibition at 2000 μg/mL, which was significantly higher than that of any individual herb (p < 0.05). Network pharmacology analysis revealed 682 common targets between HC and AD, with significant enrichment in the PI3K‑Akt signaling pathway, lipid metabolism, and chemical carcinogenesis‑receptor activation pathways, suggesting multi‑target mechanisms of action. In a D‑galactose‑induced subacute aging mouse model (3.5 g·kg[-1], 70 days), HC treatment (0.75, 1.5, and 3.0 g·kg[-1], 28 days) significantly improved spatial learning and memory in the Morris water maze. Specifically, HC at 1.5 g·kg[-1] significantly reduced escape latency (p < 0.01 vs. D‑galactose group), increased superoxide dismutase (SOD) and glutathione (GSH) levels (p < 0.05), and decreased malondialdehyde (MDA) and monoamine oxidase (MAO) levels (p < 0.01), while ameliorating hippocampal neuronal damage, as confirmed by hematoxylin and eosin staining. These findings demonstrate that HC exhibits potent anti‑cholinesterase activity, modulates oxidative stress, and protects against neuronal injury, positioning it as a promising multi‑target botanical candidate for further development in the prevention and management of AD.},
}

Animals
*Galactose
*Memory Disorders/drug therapy/chemically induced
Cognitive Enhancement
Acetylcholinesterase/metabolism
Male
Mice
Cholinesterase Inhibitors/pharmacology/therapeutic use
Maze Learning/drug effects
Signal Transduction/drug effects
Malondialdehyde/metabolism
Hippocampus/drug effects/pathology/metabolism
Oxidative Stress/drug effects
*Drugs, Chinese Herbal/pharmacology/therapeutic use

@article {pmid42759232,
year = {2026},
author = {Pocknell, C and Dinius, C and Foley, R and Commins, S and McHugh Power, J and Roche, R},
title = {Tracing dementia: Reminiscence therapy in and from place.},
journal = {Health & place},
volume = {102},
number = {},
pages = {103744},
doi = {10.1016/j.healthplace.2026.103744},
pmid = {42759232},
issn = {1873-2054},
abstract = {Across different disciplines, there has been increasing interest in the relationships between early-stage dementia, place and different forms of treatment. Reminiscence therapy has demonstrated benefits in stalling the progression of dementia, especially in its early-stage, and within such therapies, relationships between place memory and the beneficial triggering effect of place-based events and personal narratives have become important aspects. Promoting physical activity outdoors is associated with better management of dementia that additionally recognises a potential role for meaningful local places and spaces. Much of this place-based research, including go-alongs, are informed by mobile methodologies, with new spatial technologies (beyond risk-informed tracking) having much potential when used directly with patients within and outside their home places. However, there remain questions about the feasibility of using such methodologies for the purposes of place-based intervention among individuals with early-stage dementia. We document a recent proof-of-concept study, AIM-WARM, that investigated the potential impact of combining the exercise of walking and reminiscence therapy, in early Alzheimer's disease groups, to explore how such technologically-enabled place-based tools worked. Instrumental and walkability measures were augmented by digital mapping and a spatial video app, Ubipix, to capture go-alongs across familiar routes traced out within the town of Maynooth (Ireland). Specific findings identified positive results in relation to four distinct aspects of the study: walkability, cognitive instruments, the capturing of place-traces and a positive narrative response to being and moving outdoors. Additional methodological reflection considered the value of go-alongs to capture traces of people's past within their current everyday neighbourhoods, to help better understand and represent the voice of people living with dementia within community settings.},
}

@article {pmid42759802,
year = {2026},
author = {Junwu, F and Xiangqian, R and Chengyong, Y and Dai, K and Wang, J and Xiang, X and Guoqing, Z},
title = {Alzheimer's disease-associated transcriptional signatures define prognostic subtypes in glioma.},
journal = {Brain research},
volume = {},
number = {},
pages = {150525},
doi = {10.1016/j.brainres.2026.150525},
pmid = {42759802},
issn = {1872-6240},
abstract = {BACKGROUND: Gliomas are molecularly heterogeneous central nervous system tumors with marked variation in clinical outcome. Alzheimer's disease (AD)-associated transcriptional alterations may capture neural and immune programs relevant to glioma biology, but they do not by themselves establish a direct mechanistic relationship between AD and glioma.

METHODS: AD-associated differentially expressed genes were identified from GSE132903 and evaluated in TCGA/GTEx and CGGA glioma datasets. Consensus clustering, enrichment analysis, Cox and LASSO modeling, immune deconvolution, and mutation analyses were performed. The incremental prognostic value of the AD-Driven score (ADDs) was tested after adjustment for age, sex, WHO grade, IDH status, 1p/19q codeletion, and MGMT promoter methylation. Protein-expression and glioma survival annotations for the 14 model genes were reviewed in the Human Protein Atlas (HPA).

RESULTS: We identified 470 CE-associated differentially expressed genes enriched in synaptic, calcium-signaling, and neurotransmitter pathways. A 14-gene ADDs model stratified survival in the discovery and validation cohorts. Among 554 complete cases with 147 deaths, continuous standardized ADDs remained associated with overall survival after molecular and clinicopathological adjustment (HR per SD = 1.76, 95 % CI 1.26-2.44, P = 0.0008), improving model fit (likelihood-ratio P = 0.0008) but only modestly increasing the C-index (0.876 to 0.880). HPA review provided directionally supportive glioma survival annotations for seven model genes.

CONCLUSION: The ADDs captures prognostically relevant neural and immune transcriptional variation in glioma and provides incremental information beyond established molecular variables when modeled continuously. The cross-cancer IMvigor210 analysis remains exploratory and does not establish prediction of immunotherapy benefit in glioma. HPA observations provide orthogonal public-database support for selected signature components, while independent tissue-based, mechanistic, and glioma-specific treatment-response validation remain necessary.},
}

@article {pmid42760588,
year = {2026},
author = {Abdelhamid, M and Padhi, P and Gifani, M and Beck, JS and Thomas, JP and Khadse, G and Kudela, C and Phillips, GJ and Kanthasamy, AG and Counts, SE},
title = {Bioengineered microbiotic levodopa therapy improves cognition and reduces pathology in a rat model of Alzheimer's disease.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70670},
pmid = {42760588},
issn = {1476-5381},
support = {R01AG060731//National Institutes of Health (NIH)/ ; U01AG074960//National Institutes of Health (NIH)/ ; //Johnny Isakson Endowed Chair, Coach Mark Rich Endowment/ ; //Georgia Research Alliance Eminent Scholar funds/ ; },
abstract = {BACKGROUND AND PURPOSE: Degeneration of the pontine noradrenergic and midbrain dopaminergic systems contributes to cognitive-behavioural disturbances during the prodromal stages of Alzheimer's disease (AD). We developed a genetically engineered, programmable probiotic Escherichia coli Nissle 1917 strain (EcN[rha] L-DOPA) capable of producing L-3,4-dihydroxyphenylalanine (L-DOPA) in a sustained and titratable manner, thus offering a novel gut-brain delivery mechanism to increase brain levels of noradrenaline and dopamine during the early stages of AD.

EXPERIMENTAL APPROACH: We replicated locus coeruleus (LC) projection system degeneration in AD by administering dopamine-β-hydroxylase IgG-saporin immunotoxin into the prefrontal cortex of 6-months-old Tg344-19 AD rats. The animals then received EcN[rha] L-DOPA/benserazide or placebo by daily gavage for 6 weeks. We assessed cognitive-behavioural function prior to postmortem assessments of amyloid-β plaque load, glial cell activation and neuronal and synaptic markers. Gut colonization, along with plasma and brain L-DOPA, dopamine, noradrenaline and metabolite levels, were also measured.

KEY RESULTS: EcN[rha] L-DOPA displayed stable gut colonization and resulted in sustained therapeutic levels of L-DOPA in plasma and brain, resulting in increased cortical and hippocampal noradrenaline levels. EcN[rha] L-DOPA reduced anxiety-like behaviour improved spatial and working memory. The treatment reduced forebrain Aβ plaque and MHC-II antigen-presenting microglial load. Additionally, EcN[rha] L-DOPA increased protein levels of the dendritic spine marker PSD95.

CONCLUSIONS AND IMPLICATIONS: This translational study suggests that EcN[rha] L-DOPA modifies AD by boosting brain catecholamine production, reducing Aβ accumulation and neuroinflammation, promoting synaptic health, and enhancing cognitive function. Collectively, these results highlight EcN[rha] L-DOPA as a promising preclinical engineered gut microbiome-based therapeutic strategy for early-stage AD.},
}

@article {pmid42754556,
year = {2026},
author = {Wiseman, FK},
title = {New mouse models for Down syndrome Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488873},
doi = {10.1177/13872877261488873},
pmid = {42754556},
issn = {1875-8908},
abstract = {In this issue Ishihara and colleagues report the development and characterization of new mouse models for Down syndrome Alzheimer's disease, the most commonly occurring genetic cause of dementia worldwide. These new models add to the growing portfolio of in vivo models of Down syndrome. In particular, the new Ts1Kei-APPswe/PS1[dE9] model may be highly useful for the study and identification of novel treatment targets for late onset myoclonic epilepsy of Down syndrome. This seizure disorder is a common comorbidity of Down syndrome Alzheimer's disease affecting around half of all people with the condition and is associated with particularly adverse clinical outcomes.},
}

@article {pmid42755290,
year = {2026},
author = {Xu, L and Wei, N and Ran, Y},
title = {The dynamic connectome in Alzheimer's disease: From static snapshots to a symphony in time-A hypothesis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488872},
doi = {10.1177/13872877261488872},
pmid = {42755290},
issn = {1875-8908},
abstract = {The static functional connectivity (sFC) model has established Alzheimer's disease (AD) as a large-scale brain network disorder, yet it rests on a questionable assumption of temporal stationarity. This assumption obscures the brain's intrinsic dynamics, which are essential for flexible cognition. Here, we advance the hypothesis that the core deficit in AD is not merely a weakening of average connections, but a fundamental loss of the brain's capacity for temporal coordination, adaptive reconfiguration, and metastable dynamics-a state we term dynamic network dysrhythmia. Synthesizing evidence from dynamic functional connectivity (dFC) studies across the AD continuum, from subjective cognitive decline to mild cognitive impairment and AD dementia, we argue that the AD brain exhibits a progressive collapse in temporal flexibility: reduced state transition frequency, diminished connectivity variability, and entrapment in inefficient network configurations. These dynamic abnormalities correlate with molecular pathology, structural disconnection, and domain-specific cognitive deficits, positioning dFC metrics as sensitive, systems-level digital biomarkers. We further outline methodological challenges and translational opportunities for dFC in early detection, prognostic stratification, and treatment monitoring. This hypothesis reframes AD from a static disconnection syndrome to a dynamic dysrhythmia, with profound implications for both mechanistic understanding and clinical practice.},
}

@article {pmid42756205,
year = {2026},
author = {Liu, D and Zhuo, Y and Chen, S and Wang, Y and Chen, X and Yao, Y},
title = {The role of apolipoprotein E4 on calcium homeostasis in primary hippocampal neurons: an in vitro study.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1845934},
pmid = {42756205},
issn = {1662-4548},
abstract = {BACKGROUND: We previously demonstrated that apolipoprotein E (apoE4) accelerates neurodegeneration in a transgenic mouse model, but the mechanism is still unclear. A previous study reported that death-associated protein kinase 1 (DAPK1) interacts with the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor, this DAPK1-NR2B interaction increases calcium intake in cells, leading to cell damage. As apoE4 is the strongest genetic risk factor for sporadic Alzheimer's disease (sAD) and calcium dyshomeostasis is a key driver of sAD-related neurotoxicity, the unclear mechanism linking apoE4 to calcium imbalance remains a critical gap in developing targeted therapies for sAD. Addressing this gap is urgent to advance our understanding of sAD pathogenesis and identify new therapeutic targets. Our study aimed to determine whether the neurotoxic effects of apoE4 are mediated by the interaction between DAPK-1 and the NMDA receptor NR2B subunit.

METHODS: Primary mouse hippocampal neurons were cultured with apoEs in the presence or absence of an NMDA receptor antagonist that preferentially targets NR2B-containing receptors. Intracellular calcium concentration, cell viability and the proteins related to calcium homeostasis were detected.

RESULTS: Cells treated with apoE4 showed increased levels of intracellular calcium and cell death. The expression of DAPK-1 and NR2B was up-regulated, and interacted with each other under the condition of ApoE4 culture.

CONCLUSION: Our study showed that apoE4 causes neurotoxicity by increasing intracellular calcium concentration. The possible mechanism of which was that apoE4 increased the expression of DAPK-1/NMDAR2B, and further promoted the interaction between the two. These results may provide new targets and ideas for the treatment of AD.},
}

@article {pmid42754545,
year = {2026},
author = {Nanna, MG and Cohen, AB and Erickson, AC and Sun, B and Rossi, R and Akman, Z and Krishnaswami, A and Damluji, AA and Leggett, CG and Staiger, DO and Agha, L},
title = {Days Alive at Home After Emergency Department STEMI Visits Among Medicare Beneficiaries With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70705},
pmid = {42754545},
issn = {1532-5415},
support = {P30-AG021334//Johns Hopkins University Claude D. Pepper Older Americans Independence Center/ ; NIA P30-AG021334//Johns Hopkins University Claude D. Pepper Older Americans Independence Center/ ; K23-HL153771-01/HL/NHLBI NIH HHS/United States ; K76AG088428/AG/NIA NIH HHS/United States ; P01AG019783/AG/NIA NIH HHS/United States ; //American College of Cardiology Foundation/ ; /PCORI/Patient-Centered Outcomes Research Institute/United States ; P30AG021342//Yale Claude D. Pepper Older Americans Independence Center/ ; },
abstract = {BACKGROUND: As the population of older adults with Alzheimer's disease and related dementias (ADRD) increases, a growing number are presenting with acute cardiovascular events, including ST-elevation myocardial infarction (STEMI). Patient-centered outcomes following treatment for STEMI in this population are not well understood.

METHODS: This retrospective cohort study used Medicare fee-for-service claims from a 100% national sample to identify beneficiaries aged 65 years or older who presented to the emergency department (ED) with STEMI between 2017 and 2022 and underwent cardiac catheterization. Patients were stratified by ADRD status and nursing home admission source. The primary outcome was adjusted days alive at home in the year following the index ED visit. Secondary outcomes included 1-year survival, percent of alive days spent at home, and long-term nursing home care use (≥ 100 days). Multivariable linear regression models controlled for age, sex, and comorbidities.

RESULTS: Of 117,318 patients, 7348 (6.3%) had ADRD and 2617 (2.2%) were admitted from a nursing home. Among community-dwelling patients, those with ADRD had moderately lower adjusted days at home than those without ADRD (225.1 vs. 299.4; adjusted difference -37.8 days; 95% CI, -41.1 to -34.5), but more than half spent over 300 days at home. Among patients admitted from a nursing home, ADRD was associated with markedly worse outcomes (adjusted difference -71.9 days; 95% CI, -84.0 to -59.8), and 1-year survival was 42.4%.

CONCLUSION: Many community-dwelling older adults with ADRD experienced meaningful survival and time at home following cardiac catheterization for STEMI. Dementia status alone should not deter appropriate STEMI care. Treatment decisions should be individualized based on cognitive status, admission source, and patient goals.},
}

@article {pmid42754555,
year = {2026},
author = {Alcaide-Prados, MDC and Gómez-Moreno, G and Leizaola-Cardesa, IO and Moreu, G and Roa-López, A and Aguilar-Salvatierra, A},
title = {Periodontal disease and Alzheimer's disease: A systematic review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488806},
doi = {10.1177/13872877261488806},
pmid = {42754555},
issn = {1875-8908},
abstract = {BackgroundPeriodontitis is a host-mediated inflammatory disease of microbial origin that results in the loss of periodontal attachment. Its effects are not limited to the oral cavity, as association with systemic diseases, including Alzheimer's disease (AD), has been widely reported.ObjectiveTo evaluate the evidence regarding the potential relationship between periodontitis and AD through a systematic review.MethodsA bibliographic search was conducted in PubMed, Scopus, and WOS. Studies published within the last five years evaluating the biological association between both diseases were selected. The methodological quality and risk of bias of the included studies were assessed using the NOS and ROBINS-I tool, according to the study design.ResultsEleven studies were included. Eight studies analyzed biological samples obtained from brain tissue, blood/serum, saliva, gingival crevicular fluid, and cerebrospinal fluid. Patients with AD exhibited higher levels of periodontopathogenic bacteria, such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia, and an association between bacterial load and systemic inflammatory markers. Although most studies reported an association between periodontitis and AD, the findings were not consistent across studies, as some failed to identify statistically significant differences. Periodontal treatment was associated with a reduction in the AD Score, a neuroimaging surrogate marker of preclinical AD, whereas no effect was observed on brain age gap.ConclusionsEvidence suggests a possible association between periodontitis and AD through inflammatory and neurodegenerative mechanisms. Methodological limitations and study heterogeneity preclude establishing causality, underscoring the need for longitudinal studies and alternative methodological approaches.},
}

@article {pmid42751437,
year = {2026},
author = {Zhao, G and Zhou, X and Yin, S and Xu, F and Xu, L and Wang, Q and Zhou, J and Liu, S},
title = {Seven-year follow-up demonstrating sustained survival following [125]I seed brachytherapy in an elderly patient with lip squamous cell carcinoma and Alzheimer's disease: A case report.},
journal = {Oncology letters},
volume = {32},
number = {5},
pages = {490},
pmid = {42751437},
issn = {1792-1082},
abstract = {Lip squamous cell carcinoma is a distinct subtype of oral malignancy. Surgical resection provides satisfactory local tumor control; however, it frequently compromises oral function, diminishes local sensation and disfigures facial contour-sequelae are disproportionately debilitating in elderly patients with multimorbidity. This study reported the case of an 80-year-old woman with Alzheimer's disease who presented with locally advanced lip squamous cell carcinoma (cT3N2bM0, stage IVA) and cervical lymph node metastases. Following multidisciplinary team evaluation, the patient was deemed unsuitable for curative surgical resection or definitive external-beam radiotherapy. Therefore, computed tomography (CT)-guided radioactive [125]I seed implantation, assisted by a three-dimensional (3D) printed template, was performed for both the primary lip tumor and the metastatic cervical nodes, with a prescribed dose of 140 Gy. Postprocedural dosimetric verification confirmed adequate target volume coverage. The patient achieved a durable clinical complete response, with remarkable tumor regression, preserved speech and swallowing function, and remains alive with overall survival exceeding 7 years. This case demonstrates the long-term efficacy and safety of the aforementioned minimally invasive approach in an elderly patient with severe cognitive impairment-a population routinely excluded from prospective trials. No radiation-related toxicities, including xerostomia or osteoradionecrosis, were documented during follow-up. These findings indicate that CT-guided [125]I seed brachytherapy with 3D-printed templates is a feasible, function-preserving and potentially curative treatment option for carefully selected elderly patients with advanced lip squamous cell carcinoma who are unable to tolerate conventional definitive therapy. These results further challenge the common view that interventional brachytherapy serves only as a palliative measure.},
}

@article {pmid42752707,
year = {2026},
author = {Santos, DH and da Silva, AMP},
title = {Amyloid-beta-targeting monoclonal antibodies in early Alzheimer's disease: a cochrane review summary and appraisal for the neurological community.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42752707},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use ; *Amyloid beta-Peptides/immunology/metabolism ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: Seven amyloid-beta-targeting monoclonal antibodies have been trialled in early Alzheimer's disease. They differ in epitope and in how much plaque they clear; only two have traditional approval. A 2026 Cochrane Review pooled all seven as one class. We ask what that average tells us about any one drug.

METHODS: We summarise the review in mild cognitive impairment or mild dementia due to Alzheimer's disease and report its estimates and certainty ratings unchanged. Our appraisal sits in a separate section and draws on the pivotal trials and regulatory assessments.

RESULTS: Seventeen trials (20,342 participants) were included. At 18 months the pooled standardised mean difference was -0.11 (95 % confidence interval -0.16 to -0.06) for cognition and -0.12 (-0.24 to 0.00) for dementia severity; three functional scales favoured treatment (0.09 to 0.23). Amyloid-related imaging abnormalities with oedema affected 119 versus 12 per 1,000 (risk ratio 10.02, 7.49 to 13.41). Four of the seven antibodies cleared no plaque or cleared it incompletely, so the pooled result cannot test whether clearance produces benefit. In the two approved agents dementia severity differed by 0.45 and 0.67 points, larger than the class average but below thresholds of clinical importance.

CONCLUSIONS: The class average is not an estimate for any single agent. These antibodies clear amyloid and produce small differences on trial scales at 18 months, against a tenfold rise in amyloid-related oedema. Counselling should rest on agent-specific figures and a biomarker-confirmed diagnosis, and should weigh APOE ε4 genotype and antithrombotic use before the first infusion.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal/therapeutic use
*Amyloid beta-Peptides/immunology/metabolism
Cognitive Dysfunction/drug therapy

@article {pmid42752992,
year = {2026},
author = {Li, X and Liu, X and Song, X and Zhou, Y and Yang, D and Wang, Y and Mao, S and Rang, X and Hong, X and Wang, X and Yue, H and Wang, D and Zhang, X},
title = {Bioinformatics-Driven Discovery of Aβ-Targeted Therapeutics and Diagnostic Biomarkers for Alzheimer's Disease.},
journal = {BioMed research international},
volume = {2026},
number = {1},
pages = {e8975137},
pmid = {42752992},
issn = {2314-6141},
support = {LH2020H052//Heilongjiang Provincial Natural Science Foundation/ ; },
mesh = {*Alzheimer Disease/diagnosis/metabolism/genetics/drug therapy ; Humans ; *Amyloid beta-Peptides/metabolism ; *Biomarkers/metabolism ; Molecular Docking Simulation ; *Computational Biology/methods ; Curcumin/pharmacology/chemistry ; Molecular Dynamics Simulation ; Resveratrol/pharmacology ; Apigenin/pharmacology/chemistry ; Gene Regulatory Networks ; Protein Binding ; },
abstract = {The deposition of amyloid-β (Aβ) plaque is widely recognized as one of the core pathological events of Alzheimer's disease (AD). This study focused on uncovering potential diagnostic biomarkers and small-molecule candidates potentially modulating Aβ-associated pathways in AD. Weighted gene coexpression network analysis (WGCNA) and machine learning identified the hub gene. Single-nucleus RNA sequencing (snRNA-seq) identified high-expression cell clusters. We identified potential Aβ-binding small-molecule candidates and calculated their binding affinities using molecular docking techniques. Based on molecular docking, we further evaluated the binding stability and conformational dynamics of the protein-ligand complex through molecular dynamics (MD) simulations. NFKBIA was identified as a hub diagnostic gene. Three small molecules, resveratrol, curcumin, and apigenin, demonstrated strong binding affinities for NFKBIA. These findings clarify the priority candidate gene and feasible strategic directions, which are expected to be translated into practical pathways for precision diagnosis and treatment of AD.},
}

*Alzheimer Disease/diagnosis/metabolism/genetics/drug therapy
Humans
*Amyloid beta-Peptides/metabolism
*Biomarkers/metabolism
Molecular Docking Simulation
*Computational Biology/methods
Curcumin/pharmacology/chemistry
Molecular Dynamics Simulation
Resveratrol/pharmacology
Apigenin/pharmacology/chemistry
Gene Regulatory Networks
Protein Binding

@article {pmid42746205,
year = {2026},
author = {Sharif, A and Mamo, JCL and Lam, V and Luna, G and Watts, GF and Nesbit, ML and Al-Salami, H and Mooranian, A and Takechi, R},
title = {Effects of HA1, a probucol analogue, and APOC3 siRNA on lipoprotein and amyloid-β metabolism and neurovascular dysfunction in type 2 diabetic mice.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1826957},
pmid = {42746205},
issn = {1663-9812},
abstract = {INTRODUCTION: Chronic vascular exposure to elevated levels of lipoprotein-amyloid-β (Aβ) contributes to blood-brain barrier (BBB) disruption and the pathogenesis of Alzheimer's disease (AD). Therapeutic agents such as probucol have been shown to reduce circulating lipoprotein-Aβ levels and mitigate neurovascular dysfunction and cognitive decline. Type 2 diabetes (T2D) impairs BBB integrity and is characterised by dyslipidaemia and metabolic disturbances that may influence the peripheral metabolism of lipoprotein-Aβ. However, the effects of diabetes on lipoprotein-Aβ homeostasis and neurovascular integrity remain poorly understood. This study investigated whether diabetes impairs lipoprotein and Aβ metabolism and whether treatment with HA1, a probucol analogue with improved bioavailability, or APOC3 siRNA can modify these metabolic changes and improve neurovascular and behavioural outcomes.

METHODS: Non-diabetic db/+ mice, untreated diabetic db/db mice, and diabetic db/db mice treated with HA1 or APOC3 siRNA were used to determine how diabetes and therapeutic modulation of lipoprotein metabolism affect circulating Aβ, neurovascular integrity, and behavioural outcomes. Total plasma Aβ and ApoB levels were measured by ELISA. Intestinal Aβ and ApoB, neurovascular integrity, neuroinflammation, and oxidative stress were assessed by immunofluorescence. Anxiety-like behaviour and short- and long-term memory were evaluated using the open field, novel object recognition, and passive avoidance tests.

RESULTS: Diabetic db/db mice exhibited increased intestinal Aβ and ApoB immunoreactivity and elevated total plasma Aβ42, Aβ oligomer and ApoB, accompanied by heightened BBB permeability and anxiety-like phenotype. HA1 reduced intestinal Aβ and lowered plasma Aβ42 and Aβ oligomer, prevented IgG extravasation, and improved anxiety. APOC3 siRNA lowered plasma ApoB and plasma Aβ42 and attenuated neuroinflammation, but did not reduce IgG extravasation.

CONCLUSION: Dysregulated lipoprotein and Aβ metabolism are associated with neurovascular dysfunction and anxiety-like behaviour in diabetes. HA1 shows therapeutic potential by modulating Aβ metabolism and improving neurovascular and behavioural outcomes.},
}

@article {pmid42746606,
year = {2026},
author = {Liu, AJ and Moghadam, AA and Alam, MS and Lutz, MW and Navarra, A and Luo, S and Wang, LA and Petrella, JR and Whitson, H and O'Brien, RJ and Johnson, KG and Parker, D and Beam, C and Sanfilippo, M and Al-Sahlani, H and Cobb, S and Liu, MY and Doraiswamy, PM},
title = {Clinical Practice Outcomes With Lecanemab for Alzheimer Disease.},
journal = {Neurology open access},
volume = {2},
number = {3},
pages = {e000121},
pmid = {42746606},
issn = {2998-7601},
support = {P30 AG072958/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVES: Lecanemab, an antiamyloid monoclonal antibody, received US Food and Drug Administration approval in July 2023 to treat amyloid-positive early stages of Alzheimer disease (AD) and has since been adopted in many countries. The primary objective was to assess amyloid-related imaging abnormality (ARIA) incidence and serious adverse events. Secondary objectives included identifying ARIA predictors and evaluating its effect on 12-month cognitive change.

METHODS: We performed a retrospective, single-site observational study in patients treated with lecanemab at the Duke University (May 2023-June 2025). Eligible patients met National Institute on Aging-Alzheimer's Association criteria for mild cognitive impairment or mild AD with confirmed amyloid pathology. Treatment protocols and MRI interpretations were standardized.

RESULTS: Among 230 patients (68% MCI; mean age 73.6; 50.9% female; 67.4% allele producing the ε4 type of apolipoprotein E [APOE ε4] carriers), the mean follow-up was 396 days (SD 183). Forty-nine patients (21% [95% CI 16.3%-27.3%]) discontinued treatment. ARIA occurred in 56 patients (24.3% [95% CI 19.1%-30.5%]). ARIA with edema (ARIA-E) and ARIA with microhemorrhages (ARIA-MH) generally had a peak incidence rate at ~10 weeks, with a smaller ARIA-E peak at ~25 weeks; most moderate-to-severe events occurred between 12 and 24 weeks. Clinically significant adverse events occurred in 72 patients (31.3% [95% CI 25.5%-37.8%]), including 5 deaths (2 ARIA-related). Twelve-month cognitive changes did not significantly differ by ARIA status, although there was a significant decline of 0.107 [95% CI 0.04-0.17] units per month in the Montreal Cognitive Assessment score. ARIA-E risk was elevated in APOE ε4 carriers (OR 4.81 [95% CI 1.17-21.45] for 2 copies, p = 0.014) and in men (OR 2.40 [95% CI 0.88-7.25], p = 0.075). Baseline ptau-181/amyloid beta 42, APOE ε4, and Fazekas scores showed high specificity (>90%) but low sensitivity (<25%) for ARIA. Initiation of treatment earlier in the disease course was associated with fewer ARIA events, particularly among APOE ε4 noncarriers and those with lower baseline amyloid burden.

DISCUSSION: Despite the limitations of a single-site cohort, these findings inform real-world lecanemab safety and efficacy. Dual ARIA-E peaks at ~10 and ~25 weeks underscore the need for ongoing MRI monitoring. Although several markers showed modest negative predictive value, none reliably predicted ARIA. Improved markers to predict and monitor ARIA are needed to optimize cognitive outcomes.},
}

@article {pmid42746628,
year = {2026},
author = {Chen, YS and Huang, HY},
title = {Designing intranasal formulations for Alzheimer's disease: A material-based perspective.},
journal = {Tzu chi medical journal},
volume = {38},
number = {4},
pages = {446-456},
pmid = {42746628},
issn = {2223-8956},
abstract = {Alzheimer's disease (AD) remains a major global health challenge, as currently available therapies have a limited impact on disease progression and rely largely on systemic administration. Effective treatment is further hindered by the blood-brain barrier, which restricts brain exposure for most therapeutic agents. Intranasal delivery offers a noninvasive nose-to-brain approach by utilizing olfactory and trigeminal pathways to bypass systemic circulation and first-pass metabolism. Clinically, intranasal insulin and mesenchymal stromal cell-derived exosomes have demonstrated feasibility and safety in mild cognitive impairment and AD, and imaging studies have confirmed direct brain uptake following intranasal dosing. However, variable clinical outcomes suggest that therapeutic efficacy is determined primarily by formulation properties rather than by the delivery route alone. This review adopts a material-centric perspective to summarize rational intranasal formulation strategies for AD, including chitosan derivatives, thermoresponsive poloxamer and amphiphilic block copolymer platforms, lipid-based nanocarriers, surface-engineered systems, and biomimetic nanovesicles. Key translational considerations are discussed with emphasis on quantitative validation of brain exposure and reproducibility. Emerging methodological tools are briefly noted as potential facilitators of formulation development, without detracting from the central role of rational material design.},
}

@article {pmid42746961,
year = {2026},
author = {McEvoy, AM and Reeve, E and Ride, J and Langford, AV and Lee, KMK and Loh, S and Turner, J},
title = {Insomnia treatment preferences of older adults and people living with dementia: A qualitative study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261487350},
doi = {10.1177/13872877261487350},
pmid = {42746961},
issn = {1875-8908},
abstract = {BackgroundInsomnia is common in people living with dementia and older adults. While clinical guidelines recommend non-pharmacological treatment as first-line therapy, insomnia is often managed with benzodiazepine receptor agonists (BZRAs), which carry a significant risk of medication-related harm.ObjectiveTo explore what influences decisions to engage with pharmacological and non-pharmacological insomnia treatments among older adults, people living with dementia and their carers.MethodsSemi-structured interviews were conducted with three participant groups (people living with dementia, their carers, and older adults). The interviews were conducted and transcribed in Zoom. Participants identified and prioritized factors that influence their treatment decisions. Thematic analysis was conducted in NVivo to generate themes that described how participants' beliefs and experiences influenced their preferences.ResultsFrom 19 interviews with 20 participants (Median age range = 65-74 years, 37% female), 14 factors were identified. Risk of side effects (n = 10) and effectiveness (n = 7) were most commonly prioritized and frequently reported across all participant groups. Medication side effects on cognition and daytime sedation were frequent concerns. Underpinning these factors were five main themes determined from thematic analysis, including: beliefs about sleep and insomnia, treatment expectations and experiences, external influences, treatment characteristics, and barriers to treatment.ConclusionsDecisions about insomnia treatments are influenced not only by expected and/or experienced treatment effectiveness, but also by perceived risks and health beliefs. Integrating these perspectives into clinical decision-making may help reduce medication-related harm and promote safer, acceptable alternatives.},
}

@article {pmid42747078,
year = {2026},
author = {Yadav, P and Mishra, D and Singh, R},
title = {Advances in N- and S-Heterocycles as c-Jun-N-Terminal Kinase 3 Inhibitors for Alzheimer's Disease Treatment.},
journal = {Drug development research},
volume = {87},
number = {7},
pages = {e70381},
pmid = {42747078},
issn = {1098-2299},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Mitogen-Activated Protein Kinase 10/antagonists & inhibitors/metabolism ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use ; Animals ; *Heterocyclic Compounds/chemistry/pharmacology/therapeutic use ; Structure-Activity Relationship ; Drug Design ; },
abstract = {c-Jun-N-terminal kinase 3 (JNK3) inhibitors are emerging as promising therapeutic agents for the treatment of Alzheimer's disease (AD). Predominantly expressed in the central nervous system (CNS), JNK3 plays a crucial role in neuronal apoptosis and inflammation, processes that are often dysregulated in neurodegenerative conditions. In recent years, a diverse range of heterocycle scaffolds has been explored as selective JNK3 inhibitors, demonstrating significant potential in modulating disease pathology. Structure-activity relationship (SAR) studies have further facilitated the rational design and optimization of these compounds, improving their potency, selectivity, and pharmacokinetic profiles. By selectively inhibiting JNK3, these small compounds can mitigate neuroinflammation and promote neuronal survival. The development of small molecule JNK3 inhibitors offers a targeted approach that may minimize side effects. This article explores various heterocyclic molecules such as pyrazoles, thiazoles, imidazoles, and thiophenes, evaluated for JNK3 inhibition. This review will help medicinal chemists to design and develop new molecules based on established data on isoform-selective JNK3 inhibitors.},
}

Humans
*Alzheimer Disease/drug therapy
*Mitogen-Activated Protein Kinase 10/antagonists & inhibitors/metabolism
*Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use
Animals
*Heterocyclic Compounds/chemistry/pharmacology/therapeutic use
Structure-Activity Relationship
Drug Design

@article {pmid42747213,
year = {2026},
author = {Petrella, JR and Barkhof, F and Benzinger, TLS and Cogswell, PM and Franceschi, AM and Sabbagh, MN and Salloway, SP and Zaharchuk, G and Doraiswamy, PM},
title = {Artificial Intelligence-Based Detection of ARIA on MRI During Alzheimer Disease Therapy: Expert Opinion on Responsible Clinical Integration.},
journal = {AJR. American journal of roentgenology},
volume = {},
number = {},
pages = {},
doi = {10.2214/AJR.26.35514},
pmid = {42747213},
issn = {1546-3141},
abstract = {Amyloid-targeted monoclonal antibody therapies have introduced a new era in the treatment of early Alzheimer disease. However, their use has increased the importance of detecting and monitoring amyloid-related imaging abnormalities (ARIA) on MRI, as such findings may influence treatment continuation, dose modification, and patient safety assessment. As anti-amyloid therapies expand into routine practice, increasing surveillance MRI volumes, interreader variability, and the potential for missed subtle abnormalities have generated interest in artificial intelligence (AI)-based clinical decision support tools. A multidisciplinary panel of neuroradiologists and Alzheimer disease clinicians examined the extent of evidence supporting clinical implementation of AI-assisted ARIA detection tools, these tools' safe integration into practice, and remaining evidence gaps. The panel concluded that AI-assisted ARIA detection is likely to enhance patient safety when used as clinical decision support within a radiologist-in-the-loop framework. Panelists also noted substantial variation among commercially available tools in regulatory status, technical capabilities, and validation evidence. Moreover, they emphasized the need for further studies to assess the impact of improved detection on clinical outcomes. Overall, the panel supported conditional implementation with radiologist oversight, ongoing quality assurance, and prospective monitoring of clinical performance.},
}

@article {pmid42748320,
year = {2026},
author = {Izhytska, N and Sobczyk, KA and Ogrodnik, KW and Mazurkiewicz, M and Malentowicz, D and Szafraniec, NJ and Brożyna, D and Sałapski, B and Pastuszka, M},
title = {Emerging therapeutic targets beyond amyloid and tau in Alzheimer's Disease: Implications for lifestyle, metabolism and preventive medicine.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {7},
pages = {1685-1691},
doi = {10.36740/WLek/226612},
pmid = {42748320},
issn = {0043-5147},
mesh = {Humans ; *Alzheimer Disease/metabolism/prevention & control/therapy ; *tau Proteins/metabolism ; *Life Style ; *Amyloid beta-Peptides/metabolism ; Mitochondria/metabolism ; Preventive Medicine ; Microglia/metabolism ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and remains a major global health challenge. Although current disease-modifying therapies primarily target amyloid-β and tau pathology, their clinical efficacy is limited. Increasing evidence indicates that AD is a multifactorial disorder involving neuroinflammation, mitochondrial dysfunction, impaired autophagy-lysosomal pathways, and dysregulated lipid metabolism. These interconnected mechanisms contribute to disease progression and represent promising therapeutic targets. This narrative review summarizes current evidence on emerging treatment strategies beyond the classical amyloid and tau paradigm, with particular emphasis on microglial activation, mitochondrial function, autophagy, and lipid homeostasis. Additionally, the translational potential of lifestyle-based interventions, including physical activity and metabolic regulation, is discussed. A broader understanding of AD pathogenesis may support the development of integrated therapeutic approaches combining pharmacological and non-pharmacological strategies to improve clinical outcomes.},
}

Humans
*Alzheimer Disease/metabolism/prevention & control/therapy
*tau Proteins/metabolism
*Life Style
*Amyloid beta-Peptides/metabolism
Mitochondria/metabolism
Preventive Medicine
Microglia/metabolism

@article {pmid42749199,
year = {2026},
author = {Radeen, KR and Hao, C and Wei, Z and Fan, X},
title = {β-Amyloid and glutathione dysregulation cooperatively drive lipid peroxidation and ferroptosis in neuron-like cells.},
journal = {Free radical biology & medicine},
volume = {256},
number = {},
pages = {545-560},
doi = {10.1016/j.freeradbiomed.2026.09.008},
pmid = {42749199},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and oxidative stress, with aging being its greatest risk factor. Age-related glutathione (GSH) depletion may increase neuronal vulnerability to Aβ toxicity, but the underlying mechanisms remain unclear. Here, we investigated how impaired GSH homeostasis influences Aβ-associated neuronal injury. Human SH-SY5Y cells expressing either wild-type APP695 or the familial AD-associated APPSwe/Ind mutant were subjected to GSH depletion using complementary pharmacological (buthionine sulfoximine and dimethyl fumarate) and genetic (GCLC knockout) approaches. GSH depletion markedly sensitized APPSwe/Ind-expressing cells to ferroptotic cell death, characterized by increased lipid peroxidation, elevated malondialdehyde and 4-hydroxynonenal levels, enhanced lactate dehydrogenase release, increased transferrin receptor-1 expression, and intracellular iron accumulation. Cell death was prevented by ferrostatin-1, liproxstatin-1, and the iron chelator deferoxamine, but not by the pan-caspase inhibitor Z-VAD-FMK, confirming an iron-dependent ferroptotic mechanism. Similar findings were observed following co-treatment with Aβ oligomers and GSH depletion. Mechanistically, combined Aβ stress and GSH depletion were associated with increased chaperone-mediated autophagy (CMA) activity and reduced GPX4 protein levels. A photoactivatable CMA reporter demonstrated enhanced CMA activity and increased colocalization of GPX4 with CMA-associated puncta. Pharmacological inhibition of lysosomal function with bafilomycin A1 or treatment with the CMA inhibitor polyphyllin D rescued cell viability under these conditions. Collectively, these findings suggest a potential association among CMA activation, reduced GPX4 abundance, and increased susceptibility to ferroptotic cell death, providing new insight into how age-related redox imbalance may contribute to neuronal vulnerability in AD.},
}

@article {pmid42749382,
year = {2026},
author = {Conley, KB and Brown, KC and Christian, JC and Modi, KJ and Bender, CR and McGuffey, SE and Akter, S and Miles, SL and Gress, TW and Wolfer, RS and Antoniano, BD and Cummings, GH and Denning, KL and Valentovic, MA and Dasgupta, P},
title = {Memantine and its analogs: Potential applications in cancer therapy.},
journal = {Advances in cancer research},
volume = {172},
number = {},
pages = {1-74},
doi = {10.1016/bs.acr.2026.07.001},
pmid = {42749382},
issn = {2162-5557},
mesh = {Humans ; *Memantine/analogs & derivatives/therapeutic use/pharmacology ; *Neoplasms/drug therapy/pathology ; Animals ; *Antineoplastic Agents/therapeutic use ; *Drug Repositioning ; },
abstract = {Drug repurposing refers to the process of using an existing drug or drug candidate for a new treatment or medical condition for which it was not indicated before. The process of "drug repurposing" usually involves an FDA-approved entity which has undergone clinical development and have a with well-established safety and toxicity profile in patients. Several convergent studies show that repurposed drugs may present a promising strategy for the management and therapy of several human cancers. Memantine is used to combat dementia in moderate-to-severe Alzheimer's disease (AD) patients. Several convergent studies show that memantine (and its analogs) may have applications in multiple disease conditions associated with human cancers. Memantine and its related compounds have shown promise as neuroprotective agents, anti-fatigue agents and pain-relieving agents to alleviate the toxic side effects of radiation therapy and chemotherapy. Recent publications have revealed that memantine displays anti-cancer activity by exerting direct growth-suppressive activity on the primary tumor as modulating the genomic/cellular landscape of the tumor microenvironment. Currently, clinical trials are in progress, which aim to evaluate the potential applications of memantine in cancer treatment. The adamantane scaffold in memantine has proved to be a versatile tool for the discovery of synthetic memantine analogs with robust anti-cancer activity. The discovery of second-generation memantine analogs may have wider applications in combating cancer recurrence and addressing clinical challenges in the treatment of drug-resistant and metastatic cancers.},
}

Humans
*Memantine/analogs & derivatives/therapeutic use/pharmacology
*Neoplasms/drug therapy/pathology
Animals
*Antineoplastic Agents/therapeutic use
*Drug Repositioning

@article {pmid42750195,
year = {2026},
author = {Pillai, JA and Alladi, S and Appleby, BS and Brosch, JR and Frederiksen, KS and Galasko, D and Lopez, OL and Leverenz, JB and Saykin, AJ and Schott, JM and Seshadri, S and Tousi, B and Wolk, DA},
title = {Operationalizing Alzheimer's disease trials in the era of targeted therapies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71829},
doi = {10.1002/alz.71829},
pmid = {42750195},
issn = {1552-5279},
support = {P30AG072979/AG/NIA NIH HHS/United States ; P30AG066468/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; P30AG72959/AG/NIA NIH HHS/United States ; P30AG062429/AG/NIA NIH HHS/United States ; P30AG066546/AG/NIA NIH HHS/United States ; U01NS100610/NS/NINDS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/drug therapy/therapy ; Humans ; *Clinical Trials as Topic/methods ; *Antibodies, Monoclonal/therapeutic use ; Biomarkers ; Amyloid beta-Peptides ; },
abstract = {The therapeutic landscape of Alzheimer's disease (AD) is rapidly evolving with the clinical adoption of anti-amyloid monoclonal antibodies (mAbs) despite an incomplete understanding of disease mechanisms, progression, and heterogeneity. Designing both observational longitudinal cohorts and clinical trials with novel mAbs in mind is imperative. These studies should capture mAb type, dosing, duration, degree of amyloid clearance, and downstream effects on neurodegeneration to interpret outcomes. Observational cohorts can compare treated and untreated populations, track biomarker trajectories, assess co-pathologies, and evaluate social determinants of health. Future trials must address variability in treatment response, identify resistant subgroups, and include long-term follow-up to assess durability and post-treatment effects. Combination therapy trials should be stage specific, pairing novel agents with mAbs and incorporating broader stratification beyond traditional biomarkers to reflect clinical and pathological heterogeneity. Integrating biological and clinical outcomes, with digital biomarkers and responder-enrichment strategies will enable more precise, mechanism-driven, and individualized therapeutic approaches in AD.},
}

*Alzheimer Disease/drug therapy/therapy
Humans
*Clinical Trials as Topic/methods
*Antibodies, Monoclonal/therapeutic use
Biomarkers
Amyloid beta-Peptides

@article {pmid42750203,
year = {2026},
author = {Teunissen, CE and Pini, L and Imbimbo, BP},
title = {Rethinking tau-targeted therapy in Alzheimer's disease: Toward a dual biomarker strategy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71867},
doi = {10.1002/alz.71867},
pmid = {42750203},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/therapy ; *tau Proteins/metabolism ; Biomarkers/metabolism/cerebrospinal fluid ; Animals ; Positron-Emission Tomography ; },
abstract = {Tau pathology is more closely associated with cognitive deterioration than amyloid burden in symptomatic Alzheimer's disease (AD), yet tau-targeted trials have often interpreted decreases in soluble phosphorylated tau (p-tau) as evidence of therapeutic success. Emerging data argue for a more biology-informed framework. P-tau262 and p-tau356 identify sites within soluble pre-tangle tau assemblies, and cerebrospinal (CSF) p-tau262 may decline as neurofibrillary pathology advances. Conversely, marked p-tau217 lowering with posdinemab was not accompanied by clinical benefit. The amyloid field offers a useful but incomplete analogy. Amyloid plaques are extracellular whereas tau misfolding and fibrillization occur predominantly intracellularly, so equivalent relationships among imaging, fluid biomarkers, and clinical outcomes should not be assumed. A recent preprint describing a functional plasma assay of pathologically active tau reported high discrimination of tau positron emission tomography (PET) positivity, particularly at early tau PET stages, illustrating how seeding-related activity may add information beyond p-tau concentration. We propose a dual-domain framework in which tau-targeted therapies are evaluated using complementary measures of aggregated tau burden and biologically defined soluble tau states. P-tau262 is one candidate within the soluble domain, but treatment-induced increases should be considered favorable only when they accompany aggregate reduction and evidence of a less pathogenic soluble state. This framework applies across antibodies, antisense oligonucleotides, and other biologic tau-directed strategies. Future trials should test joint biomarker-clinical response functions rather than importing thresholds from anti-amyloid therapy, and should prespecify adequately powered analyses of sex, population background, disease stage, and other potential modifiers.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/therapy
*tau Proteins/metabolism
Biomarkers/metabolism/cerebrospinal fluid
Animals
Positron-Emission Tomography

@article {pmid42750750,
year = {2026},
author = {Noguchi-Shinohara, M and Ono, K},
title = {Effective amyloid clearance with lecanemab in a female with Alzheimer's disease: A case report.},
journal = {Radiology case reports},
volume = {21},
number = {12},
pages = {5973-5977},
pmid = {42750750},
issn = {1930-0433},
abstract = {Anti-amyloid monoclonal antibodies, including lecanemab, have been approved for patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease (AD). Further clarification of the long-term safety and effectiveness of these disease-modifying therapies is essential in patients treated outside the setting of clinical trials. We report an 81-year-old woman with amnestic MCI due to AD who was treated with lecanemab for 18 months in a clinical setting. At baseline, she had mild memory impairment without functional decline (Mini-Mental State Examination-Japanese version [MMSE-J], 29; Clinical Dementia Rating global score [CDR-GS], 0.5), extensive cortical amyloid deposition on [11]C-Pittsburgh compound B positron emission tomography (PET; centiloid [CL], 107.1), and elevated cerebrospinal fluid phosphorylated tau 181; she received 36 biweekly intravenous lecanemab (10 mg/kg). During treatment, surveillance magnetic resonance imaging revealed no amyloid-related imaging abnormalities, no adverse events occurred, and cognitive and functional status remained stable at 18 months (MMSE-J 28; CDR-GS 0.5), while amyloid PET demonstrated marked amyloid clearance (CL 21.3). This case illustrates substantial amyloid clearance with preserved cognitive and functional status after 18 months of lecanemab treatment without treatment-related safety concerns. Continued lecanemab therapy beyond 18 months may be feasible in carefully selected patients with early-stage AD, although further real-world data are needed to establish its long-term benefits and risks.},
}

@article {pmid42743871,
year = {2026},
author = {Guin, S and Jangli, A and Dandekar, MP},
title = {Dimethyl fumarate ameliorates amyloid-beta generated cognitive deficits by inhibiting RIPK1/RIPK3/MLKL necroptosis signalling in rats.},
journal = {International immunopharmacology},
volume = {189},
number = {},
pages = {117407},
doi = {10.1016/j.intimp.2026.117407},
pmid = {42743871},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by progressive cognitive dysfunction. Necroptosis plays a pertinent role in the neurobiology of AD, which is governed by receptor-interacting protein kinases (RIPK) and mixed lineage kinase domain-like protein (MLKL). Dimethyl fumarate (DMF), a disease-modifying drug used to treat multiple sclerosis, is also known to inhibit necroptosis pathway. Herein, we examined the effect of DMF in C6 cell line and Aβ1-42-induced AD model. DMF treatment reversed the C6 cell viability and expression of RIPK1, RIPK3, and MLKL in lipopolysaccharide model. Intracerebroventricular injection of Aβ1-42 in rats developed the cognitive deficits. Administration of DMF, at 25 and 50 mg/kg doses via peroral route for 14 days, showed a decrease in escape latency and increased exploration of target quadrant Morris water maze test. DMF-recipient rats also displayed exploration of novel object in novel object recognition test, while locomotor activity remained unchanged in open field test. DMF reduced oxidative processes by decreasing lipid peroxidation and increasing catalase and glutathione. Moreover, DMF treatment decreased the levels of IL-6, TNF-α, and CRP cytokines in frontal cortex. A significant downregulation of RIPK1, RIPK3, and MLKL gene expression and protein expression of p-MLKL were observed in the hippocampus following DMF treatment. DMF was also able to improve synaptic plasticity by increasing the expression of synaptophysin, BDNF, MBP, and PSD95, which were determined by using immunoblot. Our results indicate the cognitive improvement and neuroprotective effects of DMF in Aβ1-42 CE model by modulating the necroptosis signalling. We suggest that the selective targeting of necroptosis process may open new treatment avenues for AD.},
}

@article {pmid42743907,
year = {2026},
author = {Coskun, EP and Barber, J and Bojarski, L and McLouth, CJ and Abner, EL and Van Eldik, LJ and Nelson, PT and Jicha, GA},
title = {Autopsy findings in Alzheimer's disease clinical trial participants demonstrate a high frequency of off-target coexisting pathologic features.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100669},
doi = {10.1016/j.tjpad.2026.100669},
pmid = {42743907},
issn = {2426-0266},
abstract = {BACKGROUND: Having multiple comorbid neuropathologic features may confound the results of interventional trials that were designed to target a specific pathophysiologic mechanism in Alzheimer's disease (AD) and or related dementias (ADRD). However, it is unknown what percentage of individuals undergoing AD/ADRD interventional studies have mixed pathologies.

OBJECTIVE: To characterize the spectrum of coexisting neuropathologies in brains of AD/ADRD clinical trial participants to inform trial design and therapeutic strategies METHODS: Autopsied participants from the University of Kentucky Alzheimer Disease Research Center (UK-ADRC) community-based cohort who died between January 2005, and February 2024 were included and queried retrospectively for participation in therapeutic interventional trials. Of a total of 614 autopsied cases, 67had been enrolled in one of the following types of clinical trials: cognitively normal participants in prevention trials for AD/ADRD (designated group P; n = 21); interventions for mild cognitive impairment or early dementia (MCI/D; n = 26); and, interventions for vascular cognitive impairment (V; n = 20). The trial-engaged groups were compared to the trial-naïve group in terms of their demographic, clinical, and genetic characteristics. Pathological features (amyloid-β, tau, α-synuclein, TDP-43, and cerebrovascular disease) were assessed using consensus-based neuropathologic methods.

RESULTS: All interventions were designed to target only a single pathologic feature. The trial-engaged group did not differ significantly from those who were trial-naïve with respect to demographic, genetic (APOE), or clinical characteristics, except for a marginally higher level of education among trial participants (p=0.04). Pure on-target pathology (i.e., only one isolated pathology was found at autopsy that was the signature pathology targeted by the intervention) was only seen in 10, 23, and 29 % of the engaged participants of V, MCI/D and P trials respectively. Comorbid pathologies were common in all three groups. On average, the trial-engaged groups altogether had a mean of 2.54 pathologic features/person, whereas the MCI/D trial-engaged group had a mean of 3.2 pathologic features/person.

CONCLUSION: Multi-etiology dementia was the norm rather than the exception for AD/ADRD trial participants. Recognizing the heterogeneity of multiple pathologies in clinical trial participants may enable the development of improved inclusion/exclusion criteria, as well as the rational use of antemortem biomarkers to stratify the likelihood of mixed comorbid pathologies that may be undesirable for single-target interventional studies. Further, multitargeted treatment strategies may be required in future trials of disease-modifying agents.},
}

@article {pmid42744009,
year = {2026},
author = {Chen, X and Fu, P and Kang, C and Wu, Y and Wu, Y and Luo, X and Chen, L and Liu, H and Ouyang, J and Zhang, M and Yin, X and Chen, Z},
title = {The mechanism of cerebellar involvement in cognitive disorders and therapeutic prospects.},
journal = {Experimental gerontology},
volume = {225},
number = {},
pages = {113324},
doi = {10.1016/j.exger.2026.113324},
pmid = {42744009},
issn = {1873-6815},
abstract = {The cerebellum has traditionally been regarded as a brain region primarily involved in motor coordination and balance. However, increasing evidence suggests that the cerebellum plays a significant role in multiple higher-order cognitive functions. This review explores the mechanisms underlying cerebellar involvement in cognitive impairment, focusing on four prevalent cognitive disorders: Alzheimer's disease, vascular cognitive impairment, Parkinson's disease dementia, and frontotemporal dementia. Analysis of existing neuroimaging, neuropathological, and clinical studies indicates that cerebellar structural and functional abnormalities constitute a common pathological feature of cognitive dysfunction in these conditions. Deepening our understanding of cerebellar-cerebral interactions offers new perspectives for early diagnosis, disease monitoring, and therapeutic interventions in cognitive disorders. This review also summarizes research on the cerebellum as a potential target for non-invasive brain stimulation therapy, which holds promise for opening up new avenues for intervention in cognitive disorders and ultimately leading to better treatment outcomes and quality of life for patients.},
}

@article {pmid42744302,
year = {2026},
author = {Reskiawan A Kadir, R and Bons, J and Vega Hormazabal, G and Vadhana Ashok Kumaar, P and Gerónimo-Olvera, C and Tshilenge, KT and Pihán, P and Galicia Aguirre, C and Schneider, K and Roberts, A and Ambrose, BD and Lerner, C and Devanney, NA and Sandholm, AM and Hady, M and Alderfer, S and Hetz, C and Furman, D and Gerencser, AA and Verdin, E and Schilling, B and Ellerby, LM},
title = {The longevity gene APOE2 enhances pericyte function and reduces lipid droplets.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag311},
pmid = {42744302},
issn = {1460-2156},
abstract = {Pericytes are critical for maintaining blood-brain barrier (BBB) integrity and have emerged as key contributors to Alzheimer's disease (AD) pathogenesis. Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear. We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity. To uncover the underlying mechanisms, we used CRISPR/Cas9 editing to generate isogenic human iPSC-derived pericytes carrying APOE2, APOE3, or APOE4 alleles. All lines expressed pericyte markers in an APOE allele-dependent levels. Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity. Further, APOE2 pericytes exhibited increased resistance to senescence and reduced amyloid-β accumulation. Using unbiased proteomic profiling to understand these cellular phenotypes, we found significant alterations in lipid metabolism-related proteins. Untargeted lipidomic analysis confirmed a genotype-specific lipid signature, observing reduced phospholipids and increased triglycerides in APOE2 pericytes. Interestingly, APOE2 pericytes showed lower lipid droplet (LD) accumulation. Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing. Notably, recombinant APOE2 treatment effectively rescued pericyte function and mitigated LD accumulation in APOE3 and APOE4 pericytes. Collectively, these findings demonstrate that APOE2 expression supports pericyte functionality through increased lipid processing, providing mechanistic insight into the cerebrovascular protective effects of APOE2 in pericytes. These findings could be translated into novel therapies aimed at enhancing pericyte function and lipid metabolism, particularly in individuals at risk for neurodegenerative diseases.},
}

@article {pmid42745524,
year = {2026},
author = {Chandrasekaran, A and Paget-Blanc, A and Decourt, B and Sabbagh, MN},
title = {Investigating oral blarcamesine for treatment of early Alzheimer's disease.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {},
doi = {10.1080/14656566.2026.2732056},
pmid = {42745524},
issn = {1744-7666},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative dementia affecting millions globally. Therapies primarily consist of symptomatic management and progression limitation. Further advances in treatments include disease-modifying therapies, many of which have unfavorable safety profiles and modest improvements in cognitive function. The need for novel disease-modifying therapies continues to grow as the burden of AD in the population increases.

AREAS COVERED: We outline approved disease-modifying therapies including the mechanisms of autophagy restoration through SIGMAR1 activation and its impact on neuronal homeostasis, and how oral blarcamesine, a SIGMAR1 agonist, demonstrates promise for early onset AD management. We then describe the Phase IIa and IIb/III clinical trials supporting the efficacy of blarcamesine in AD patients and other neurodegenerative diseases. Additionally, we discuss recent preclinical evidence supporting a preventive role for blarcamesine in AD. A Pubmed search was conducted for relevant literature regarding this topic using keywords including, but not limited to, 'blarcamesine,' 'disease-modifying therapy,' 'precision medicine,' 'sigma-1 receptor,' and 'SIGMAR1 agonist.'

EXPERT OPINION: Blarcamesine is a potential oral disease-modifying therapeutic candidate for early-stage AD that acts upstream of amyloid-beta pathogenesis and could prevent AD progression very early on, with emerging preclinical evidence also supporting its potential for disease prevention.},
}

@article {pmid42745714,
year = {2026},
author = {Ikeda, M},
title = {[How to Proceed with Diagnosing Memory Loss].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {78},
number = {9},
pages = {1003-1014},
doi = {10.11477/mf.188160960780091003},
pmid = {42745714},
issn = {1881-6096},
mesh = {Humans ; *Memory Disorders/diagnosis ; Diagnosis, Differential ; Alzheimer Disease/diagnosis ; *Dementia/diagnosis ; Cognitive Dysfunction/diagnosis ; },
abstract = {When diagnosing dementia disorders, obtaining a detailed medical history and identifying relevant findings on physical and neurological examinations are fundamental. It is essential to assess cognitive function, neurological symptoms and signs, and dementia severity; conduct additional tests; and establish a differential diagnosis. With the widespread use of anti-amyloid antibody therapies, mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and early-stage AD must not be overlooked. When evaluating patients with dementia who present with diverse symptoms, clinicians must consider neurological signs, findings from diagnostic tests, and the clinical course to establish an accurate diagnosis and guide appropriate treatment.},
}

Humans
*Memory Disorders/diagnosis
Diagnosis, Differential
Alzheimer Disease/diagnosis
*Dementia/diagnosis
Cognitive Dysfunction/diagnosis

@article {pmid42746101,
year = {2026},
author = {Ray, WJ and Lightfoot, YL and Trinh, RT and Fawver-Kahle, J and Cooper, S and Tsai, LH and Bortz, J and Trujillo-Gonzalez, I and Zhang, T and Wu, H and Iv, GJO and Schulz, PE},
title = {Effect of choline supplementation in presymptomatic APOE ε4 carriers: a pilot study.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70323},
pmid = {42746101},
issn = {2352-8737},
abstract = {INTRODUCTION: With the advent of early detection biomarkers, it is possible to envision testing preventive strategies that delay the onset of Alzheimer's disease (AD). The ε4 allele of apolipoprotein E (APOE ε4) is the strongest genetic risk factor for late-onset AD; approximately 50% of all patients are APOE ε4-positive.[1] APOE is the major central nervous system (CNS) lipoprotein, and studies have linked APOE4-dependent deficits in lipid metabolism to disease-relevant processes.[2-6] Choline, the precursor for phosphatidylcholine (PC), normalizes APOE ε4-mediated lipid dysfunction in human model systems,[6] and low dietary choline intake correlates with increased disease risk or progression in mouse models and humans.[7-17] We therefore tested whether biomarkers and omics provided early evidence of choline CNS target engagement in an at-risk population.

METHODS: In a 6-month open-label phase 1 study (NCT05880849), asymptomatic APOE ε4 carriers (n = 13; age 70 ± 5.5 years) received 2200 mg/day oral choline, with plasma and cerebrospinal fluid (CSF) collected before and after treatment.

RESULTS: Choline was well tolerated with no serious adverse events. Treatment increased plasma and CSF choline and betaine, indicating systemic and CNS exposure. Exploratory lipidomics identified changes in plasma PC species and, in CSF, increases in ceramides and cholesterol esters. Although this study was not powered to assess biomarker efficacy, CSF neurofilament light (NfL) was lower at the end of treatment, and CSF phosphoserine-181 tau (pTau181)/amyloid beta (Aβ)42 and plasma pTau217 showed directionally similar trends.

DISCUSSION: These findings support randomized placebo-controlled trials of choline in at-risk populations and illustrate how fluid biomarkers and omics can de-risk AD prevention studies.},
}

@article {pmid42734057,
year = {2026},
author = {Jang, S and Chen, J},
title = {Hospital Artificial Intelligence Tools and Inpatient Utilization and Costs in Older Adults with Alzheimer's Disease and Related Dementias.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70704},
pmid = {42734057},
issn = {1532-5415},
support = {P30AG097158/AG/NIA NIH HHS/United States ; RF1AG083175/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Hospitals are increasingly adopting artificial intelligence and machine learning (AI/ML) tools to support clinical decision making and care management. However, evidence on how hospital AI/ML adoption relates to inpatient utilization and spending among clinically complex populations remains limited. Older adults with Alzheimer's disease and related dementias (ADRD) experience higher rates of readmissions and potentially avoidable hospitalizations.

METHODS: Cross-sectional study was conducted using 2023 inpatient claims linked to the Medicare Beneficiary Summary File and the American Hospital Association Annual Survey Information Technology Supplement to examine associations between hospital adoption of patient-related AI/ML tools and inpatient utilization and spending among Medicare fee-for-service (FFS) beneficiaries with ADRD. The study included 340,509 FFS beneficiaries aged 65 years or older with ADRD who experienced at least one inpatient hospitalization in 2023. Hospital adoption of patient-related AI/ML tools was measured using four indicators reflecting AI/ML use to predict inpatient health risks, identify high-risk outpatients, monitor patient health, and recommend treatments. Outcomes included frequent hospitalization, 30-day readmission, preventable acute and chronic hospitalizations, total Medicare payments, and beneficiary out-of-pocket (OOP) spending. Multivariable regression models adjusted for beneficiary and hospital characteristics.

RESULTS: Greater hospital adoption of patient-related AI/ML tools was associated with lower odds of frequent hospitalizations, 30-day readmissions, and preventable acute hospitalizations. Inpatient risk prediction and high-risk outpatient identification tools were consistently associated with lower inpatient utilization. Inpatient risk prediction was associated with lower total Medicare spending, while high-risk outpatient identification was associated with higher Medicare spending. Treatment recommendation tools were associated with higher beneficiary OOP spending.

CONCLUSIONS: Among Medicare FFS beneficiaries with ADRD, hospital adoption of patient-related AI/ML tools, particularly those focused on risk prediction and high-risk patient identification, was associated with lower inpatient utilization without increasing overall spending. Heterogeneity across AI/ML tool types suggests the importance of evaluating AI/ML tools based on their specific clinical functions.},
}

@article {pmid42735882,
year = {2026},
author = {Ma, X and Li, W and Ma, Y and Ma, W and Han, Z},
title = {Triptolide preserves cognitive function and reduces hippocampal inflammation in a mouse model of Alzheimer's disease.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104126},
doi = {10.1016/j.mcn.2026.104126},
pmid = {42735882},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that affects an estimated 50 million people worldwide. This remains a significant medical challenge. Despite the availability of numerous therapeutic agents, they are often only partially effective, highlighting the urgent need for the development of more effective next-generation drugs. Triptolide (T10), a key bioactive compound found in traditional Chinese medicine, is renowned for its wide range of pharmacological properties, including promising neuroprotective effects observed in vitro. However, its therapeutic effects and underlying mechanisms in the 5xFAD mouse model, particularly regarding microglial-mediated neuroinflammation, remain incompletely characterized. This study explored the impact of peripherally administered T10 on AD-associated behaviors and neuroinflammation in 5xFAD mice. The findings indicate that a 45-day T10 regimen significantly improved cognitive impairment in mice. Immunohistochemical analyses further demonstrated that T10 treatment markedly decreased Iba1-positive cell density in the CA1 region of the hippocampus and reduced immune and inflammatory responses in this region. Transcriptomic profiling suggests that T10 modulates cognitive function in 5xFAD mice via inflammatory signaling pathways. Taken together, these results suggest that T10 improves learning and cognitive performance and reduces hippocampal inflammatory responses in 5xFAD mice, supporting its further investigation as a potential therapeutic intervention for AD.},
}

@article {pmid42736378,
year = {2026},
author = {Thomassen, JQ and Leonard, H and Ulms, B and Grenier-Boley, B and Heikkinen, S and Garcia-González, P and Castillo-Morales, A and Kikuchi, M and Gim, J and Cao, H and Küçükali, F and Amin, N and Yoon, D and de Rojas, I and Alvarez Jerez, P and Alvarez, V and Arosio, B and Bellenguez, C and Bergh, S and Billingsley, K and Blauwendraat, C and Boada, M and Borroni, B and Bossù, P and Bullido, MJ and Daniele, A and Carracedo, Á and de Mendonça, A and Cookson, M and Deckert, J and Dichgans, M and Djurovic, S and Dols-Icardo, O and Dufouil, C and Düzel, E and Escott-Price, V and Fladby, T and Fratiglioni, L and Fu, AKY and Galimberti, D and García-Alberca, JM and Giedraitis, V and Garcia-Ribas, G and Graff, C and Grimmer, T and Grünblatt, E and Hanon, O and Hausner, L and Heilmann-Heimbach, S and Hort, J and Jessen, F and Jensen, K and Jonson, C and Kim, Y and Kuznetsov, N and Leinonen, V and Lipponen, A and Luo, J and Makarious, M and Martiskainen, H and Masullo, C and Mecocci, P and Mehrabian, S and Mir, P and Miyashita, A and Moebus, S and Mok, KY and Molina Porcel, L and Moreno, F and Nacmias, B and Parnetti, L and Pastor, P and Pérez-Tur, J and Peters, O and Pijnenburg, YAL and Piñol-Ripoll, G and Popp, J and Rainero, I and Real, LM and Riedel-Heller, S and Rodriguez-Rodriguez, E and Rongve, A and Rossi, G and Royo, JL and Rujescu, D and Saltvedt, I and Sáez, ME and Sánchez-Valle, R and Sanchez-Garcia, F and Sandau, N and Scarmeas, N and Scheffler, K and Scherbaum, N and Schneider, A and Selbæk, G and Seripa, D and Solfrizzi, V and Spallazzi, M and Squassina, A and Stordal, E and Tesi, N and Tremolizzo, L and Tripathi, KP and van der Flier, WM and Williams, J and Wiltfang, J and Aarsland, D and Singleton, AB and Amouyel, P and Debette, S and Tsolaki, M and Nicolas, G and van der Lee, S and Holstege, H and Fernandez, MV and Kehoe, PG and Sleegers, K and Ingelsson, M and Ghidoni, R and Andreassen, OA and Holmans, PA and Sánchez-Juan, P and Sims, R and Ip, NY and Lee, KH and Ikeuchi, T and Ramirez, A and Ruiz, A and Hiltunen, M and Lambert, JC and van Duijn, C and Nalls, M and Frikke-Schmidt, R},
title = {APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {42736378},
issn = {1546-1718},
abstract = {Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies[1-10]. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers[11-13], hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.},
}

@article {pmid42736653,
year = {2026},
author = {Yadav, R and Sinha, J and Deeksha, K},
title = {Beyond the Single-Target Approach: Polypharmacology and Multi-Target Therapeutics in Alzheimer's Disease.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249497051260829094309},
pmid = {42736653},
issn = {1875-6166},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-beta aggregation, tau pathology, oxidative stress, neuroinflammation, mitochondrial dysfunction, and synaptic degeneration. The limited clinical success of traditional single-target therapeutic approaches has highlighted the need for more comprehensive treatment strategies. Polypharmacology has emerged as a promising paradigm that seeks to simultaneously modulate multiple pathological pathways involved in disease progression. In particular, multi-target-directed ligands (MTDLs) have gained considerable attention due to their ability to integrate multiple pharmacological activities within a single molecular entity. This review summarizes current advances in polypharmacology-based approaches for Alzheimer's disease, including rational drug design, ligand-based and network pharmacology strategies, artificial intelligence-assisted drug discovery, and emerging multi-target therapeutics. Representative synthetic and natural-productderived MTDLs are critically evaluated with respect to their mechanisms of action, pharmacokinetic limitations, blood-brain barrier penetration, and clinical development status. Finally, major translational challenges and future opportunities are discussed. Collectively, polypharmacology represents a promising framework for developing next-generation disease-modifying therapies for Alzheimer's disease, although significant challenges remain before widespread clinical implementation can be achieved.},
}

@article {pmid42736672,
year = {2026},
author = {Nadeem, MS and Rahman, S and Murtaza, BN and Al-Zharani, M and Afzal, M and Nasr, FA and Iftikhar, S and Chaieb, K and Alzarea, SI and Kazmi, I},
title = {The Microbiome-Gut-Brain Axis: Decoding the Molecular Dialogue for Next-Generation Neurotherapeutics.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X491341260902051725},
pmid = {42736672},
issn = {1875-6190},
abstract = {The human brain has traditionally been considered an isolated organ until the establishment of the microbiome-gut-brain axis (MGBA) overturned that concept. Based on recent reports, the present review provides confirmatory evidence that there is a complex communication in the MGBA that links the central nervous system with the resident microbial community of the gastrointestinal tract. A complex, highly sophisticated molecular dialogue involving immune and neuroinflammatory molecules, signaling via the vagus nerve and neural pathways, and key metabolic and endocrine routes facilitates cross-talk between the brain and the gut microbiome. Crucial microbial metabolites, such as bile acids and short-chain fatty acids (SCFAs), neurotransmitter release, and modulation of systemic inflammation are highlighted as primary mediators of gut-brain interactions. In recent times, research has shifted from establishing associations to elucidating precise mechanisms between brain physiology and the composition of the gut microbial community. Recent studies have emphasized linking specific bacterial taxa to neurological outcomes in Alzheimer's disease (AD), Parkinson's disease (PD), and autism spectrum disorder (ASD). Emerging therapeutic modalities such as engineered live biotherapeutics, next-generation psychobiotics, precision nutrition, and fecal microbiota transplantation are promising avenues for next-generation neurotherapeutics. However, the path to clinical translation is fraught with challenges, including methodological heterogeneity and reproducibility, establishing causality, and confounding host factors. This review concludes with a forward-looking roadmap that emphasizes multi-omics integration, standardization, human-relevant disease models, and personalized therapeutic strategies to decode the MGBA and exploit its full potential, which could revolutionize the treatment of brain disorders.},
}

@article {pmid42739229,
year = {2026},
author = {Rahmani, AH and Sarwar, T},
title = {Artificial Intelligence and Digital Biomarkers for Early Detection and Monitoring of Neurological Disorders: A Narrative Review.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {17},
pages = {},
pmid = {42739229},
issn = {2075-4418},
abstract = {Neurological disorders like Alzheimer's disease, Parkinson's disease, and epilepsy are becoming major causes of disability and mortality worldwide, and their prevalence is expected to rapidly increase with the aging of the population. These diseases develop silently, with irreversible neuronal damage often occurring decades before any clinical signs of illness are noticed, making early diagnosis and treatment difficult. The presymptomatic period greatly restricts the effectiveness of therapeutic interventions and reduces the possibility of disease-modifying interventions. Traditional diagnostic methods based on clinical assessment, neuroimaging, and invasive biomarkers are not sensitive enough to identify the disease at an early stage and are expensive to the healthcare system. The latest artificial intelligence (AI) technology and machine learning (ML) approaches, together with digital biomarkers obtained from eye tracking, facial expressions, speech analysis, motor dynamics, electrophysiology, wearable devices, and passive sensing, offer promising non-invasive alternatives for early detection of diseases. However, most reported performance metrics are derived from retrospective or pre-validated datasets, and prospective external validation remains limited. This narrative review synthesizes current evidence on AI-driven digital biomarkers for early detection of neurological diseases, examining disease-specific applications, methodological approaches, and challenges in clinical practices. We emphasize that clinical utility is task specific and dependent on disease stage, validation design, clinical endpoints, cost, workflow integration, and availability of disease-modifying therapies. We also note that much of the evidence summarized here derives from retrospective, case-control, or internally validated datasets and that prospective, patient-independent, and external validation with clinically meaningful endpoints remains limited. Reported performance figures should be read as proof-of-concept evidence rather than as evidence of demonstrated clinical readiness. We highlight promising future directions, including federated learning, explainable AI, and precision neurology approaches, while acknowledging that most applications remain investigational and require prospective validation before broad clinical deployment.},
}

@article {pmid42739787,
year = {2026},
author = {Kalampokini, S and Keramidiotis, I and Frontistis, A and Zuchi, F and Michmizos, D and Papaliagkas, V and Koutsouraki, E},
title = {Anti-Amyloid Antibodies in the Treatment of Alzheimer's Disease: An Umbrella Review.},
journal = {Journal of clinical medicine},
volume = {15},
number = {17},
pages = {},
pmid = {42739787},
issn = {2077-0383},
abstract = {Background: Over the last decade, numerous studies have investigated the administration of monoclonal anti-amyloid antibodies (AAAs) as a therapeutic approach in Alzheimer's disease (AD). The purpose of this umbrella review is to summarize current knowledge concerning the efficacy and safety of FDA- and EMA-approved AAAs for AD, namely, lecanemab and donanemab. Methods: We conducted a literature search in the PubMed, Scopus, and Web of Science databases in English, focusing on systematic reviews and/or meta-analyses, assessed by AMSTAR 2, concerning clinical and imaging efficacy, i.e., cognitive improvement and reduction of beta-amyloid on PET scan, as well as safety, i.e., adverse events and amyloid-related imaging abnormalities (ARIA). The extracted review-level dataset was entered into SPSS Version 26 for descriptive statistical analysis. Results: This umbrella review included 11 systematic reviews and/or meta-analyses. Patients treated with lecanemab or donanemab showed statistically significant changes on cognitive scales such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB) (mean effect estimate -0.485, SD = 0.152, -0.70 to -0.34) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), but most were below or around clinically meaningful thresholds. Lecanemab and donanemab showed a statistically significant decrease in amyloid PET outcomes, including centiloids or the standardized uptake value ratio. Both antibodies were linked to ARIA, including amyloid-related imaging abnormalities-edema (ARIA-E OR 8.32-12.26) and amyloid-related imaging abnormalities-hemorrhage (ARIA-H OR 2-5.77), especially in ApoEε4 carriers. Conclusions: Lecanemab and donanemab are biologically active drugs for the treatment of early AD, with cognitive benefits below or around the clinically meaningful threshold. They are, however, associated with increased ARIA risk. Their administration depends upon careful patient selection, shared decision-making, and clear communication regarding expectations.},
}

@article {pmid42741217,
year = {2026},
author = {Chen, Y and Shi, J},
title = {Serum metabolomic profiling following cerebellar repetitive transcranial magnetic stimulation combined with cognitive training on Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1887127},
pmid = {42741217},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/therapy/blood ; *Cognitive Training ; *Transcranial Magnetic Stimulation/methods ; Female ; Male ; Metabolomics ; Biomarkers/blood ; Aged ; *Cerebellum ; Combined Modality Therapy ; *Metabolome ; },
abstract = {BACKGROUND: Complex metabolic disorders are a key characteristic of Alzheimer's disease (AD). Although studies have shown that combining repetitive transcranial magnetic stimulation (rTMS) with cognitive training (CT) can alleviate AD symptoms, the specific pathophysiological processes involved remain poorly understood. Our goal is to analyze metabolomic changes associated with bilateral cerebellar rTMS plus CT in AD treatment, to identify potential biomarkers of disease progression and therapeutic outcomes, and to validate these findings against a systematic review of existing literature.

METHODS: We enrolled 12 individuals with early AD and 12 healthy controls (HC). The AD group received 2 weeks of bilateral cerebellar rTMS combined with CT. We performed ultra-high-performance liquid chromatography-tandem mass spectrometry analysis on serum samples obtained from AD patients (before and after intervention) and HC. The PubMed database was used to conduct a systematic review of AD metabolomics literature, from which differential metabolites were identified and analyzed using pathway enrichment analysis.

RESULTS: A total of 510 metabolites were differentially expressed in response to treatment, with 202 consistent with improved clinical status. Fourteen pathways were enriched, including those involved in valine, leucine, and isoleucine biosynthesis, as well as glycine, serine, and threonine metabolism, which are linked to the pathology and treatment of AD. Metabolites such as lysophosphatidylcholine (22:6) and citric acid, increased after treatment and shifted toward healthy control levels, whereas γ-guanidinobutyric acid, proline, decreased after treatment. Systematic review analysis suggested Phenylalanine as a potential biomarker for AD screening at the mild cognitive impairment stage.

CONCLUSION: This study's integrative analysis offers preliminary insights into treatment-associated metabolic alterations in AD and identifies candidate metabolites for further investigation as markers of disease status and treatment response.

TRIAL REGISTRATION: ChiCTR2200061754.},
}

Humans
*Alzheimer Disease/therapy/blood
*Cognitive Training
*Transcranial Magnetic Stimulation/methods
Female
Male
Metabolomics
Biomarkers/blood
Aged
*Cerebellum
Combined Modality Therapy
*Metabolome

@article {pmid42741654,
year = {2026},
author = {Tansey, MG and Bozeat, S and Ackerman, P and Atri, A and Barnum, CJ and Brundin, P and de Carvalho, CA and Fleisher, AS and Graf, A and Head, E and Kerchner, GA and Kolb, HC and Koyama, A and Kozberg, M and Leyns, CEG and Llibre-Guerra, JJ and Mattsson-Carlgren, N and McKissock, D and Murray, ME and Rosenthal, LS and Rubel, C and Schindler, SE and Schneider, JA and Schwarz, AJ and Scott, KM and Seredenina, T and Tosun, D and Wallings, RL and Wang, H and Wilcock, DM and Carrillo, M and Mahinrad, S and Weber, CJ},
title = {Alzheimer's disease heterogeneity and co-pathologies: Defining novel targets, biomarkers, modalities, and research methodologies.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {3},
pages = {e70287},
pmid = {42741654},
issn = {2352-8737},
abstract = {Alzheimer's disease (AD) is a biologically heterogeneous condition with vascular, proteinopathic, metabolic, and immune processes jointly shaping its clinical expression, trajectory of progression, and response to therapeutic intervention. Common AD co-pathologies such as cerebral amyloid angiopathy, Lewy body pathology, α-synuclein, and transactive response DNA-binding protein of 43 kDa (TDP-43)/limbic-predominant age-related TDP-43 encephalopathy are also increasingly connected with cognitive decline and therapeutic response. Significant advances in biomarkers, including seed amplification assays, proteomic signatures, and emerging positron emission tomography tracers bolster the field's understanding of a biological staging model and discovery of previously unrecognized co-pathologies. The Fall 2025 Alzheimer's Association Research Roundtable (AARR) brought together academic, clinical, and industry leaders to discuss and explore the current advances in the heterogeneity and co-pathologies of AD, and their implications for diagnosis, clinical trial design, and precision treatment strategies. This paper presents key takeaways from the Fall 2025 AARR meeting.},
}

@article {pmid42741980,
year = {2026},
author = {Vanderlip, CR and Stark, CEL},
title = {Digital cognitive phenotyping enhances risk stratification in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {9},
pages = {e71834},
pmid = {42741980},
issn = {1552-5279},
support = {/NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; Female ; Aged ; Phenotype ; Male ; tau Proteins/blood ; Disease Progression ; Positron-Emission Tomography ; Amyloid beta-Peptides ; Risk Assessment/methods ; *Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; Prodromal Symptoms ; Aged, 80 and over ; Biomarkers/blood ; Digital Health ; },
abstract = {INTRODUCTION: Amyloid positivity does not reliably predict near-term cognitive decline in preclinical Alzheimer's disease (AD). We tested whether digital cognitive phenotyping improves prognostic precision.

METHODS: Baseline performance on a brief self-administered digital battery was analyzed in 1146 amyloid beta (Aβ)+ and 538 Aβ- cognitively unimpaired older adults from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies. Unsupervised k-means clustering identified cognitive phenotypes. Survival models examined time to Preclinical Alzheimer Cognitive Composite decline and Clinical Dementia Rating (CDR) progression. Associations with tau positron emission tomography and plasma phosphorylated tau (p-tau)217 were evaluated.

RESULTS: Four cognitive phenotypes emerged. One phenotype (18% of Aβ+ participants) showed the steepest cognitive decline, highest progression on the CDR, greater baseline medial temporal tau, and fastest neocortical tau accumulation over 4.6 years (hazard ratio [HR] for decline ≈ 2.9). Combining this phenotype with elevated plasma p-tau217 identified a subgroup at markedly amplified risk (HR ≈ 4.5).

DISCUSSION: Digital cognitive phenotyping, especially when integrated with plasma biomarkers, identifies actionable risk heterogeneity and enables scalable precision prognostication in preclinical AD.},
}

Humans
*Alzheimer Disease/diagnosis
Female
Aged
Phenotype
Male
tau Proteins/blood
Disease Progression
Positron-Emission Tomography
Amyloid beta-Peptides
Risk Assessment/methods
*Cognitive Dysfunction/diagnosis
Neuropsychological Tests
Prodromal Symptoms
Aged, 80 and over
Biomarkers/blood
Digital Health

@article {pmid42742530,
year = {2026},
author = {Takahashi, R and Kashibayashi, T and Fujita, J and Yoshida, K and Hashiramoto, A and Kowa, H and Mizuta, E},
title = {Lower baseline cerebrospinal fluid amyloid-β 42 is associated with amyloid-related imaging abnormalities during real-world lecanemab treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488874},
doi = {10.1177/13872877261488874},
pmid = {42742530},
issn = {1875-8908},
abstract = {Amyloid-related imaging abnormalities (ARIA) are a safety concern during lecanemab treatment for early Alzheimer's disease. We examined baseline cerebrospinal fluid amyloid-β 42 (Aβ42) in 97 lecanemab-treated patients; 11 developed ARIA. Aβ42 was lower in ARIA cases than in non-ARIA cases (483.2 ± 108.6 versus 667.4 ± 185.4 pg/mL; p < 0.001). ROC analysis yielded an AUC of 0.806 (95% CI, 0.670-0.919). Aβ40 was also lower, whereas the Aβ42/Aβ40 ratio was not significantly different and tau biomarkers were not higher. Lower Aβ42 was associated with subsequent ARIA, but the internally derived cutoff requires external validation.},
}

@article {pmid42742914,
year = {2026},
author = {Perneczky, R and Jessen, F and Grimmer, T and Levin, J and Hufnagel, A and Flöel, A and Peters, O and Froelich, L and Hofmann, A and , },
title = {From Proof of Principle to Therapeutic Discipline: Strategies to Improve the Benefit/Risk Profile of Amyloid-Targeting Treatments for Alzheimer's Disease.},
journal = {CNS drugs},
volume = {},
number = {},
pages = {},
pmid = {42742914},
issn = {1179-1934},
abstract = {The first generation of clinically approved amyloid-targeting treatments has changed the terms of debate in Alzheimer's disease. It is no longer persuasive to argue that amyloid removal is biologically irrelevant or clinically inert in early symptomatic Alzheimer's disease. Lecanemab and donanemab have both demonstrated statistically robust and clinically meaningful, albeit still modest, slowing of disease progression, thereby establishing disease modification as a realistic therapeutic objective rather than a speculative aspiration. At the same time, these agents have exposed the defining limitation of the current therapeutic concept: although clearly beneficial for some patients, the margin for benefit versus risk remains narrow, and its realization in routine care is operationally demanding and heavily dependent on careful patient selection and surveillance rather than on drug effect alone. The central task for the field is therefore no longer to prove that amyloid-targeting treatments can work, but to make them work more effectively, more safely, more targeted, and less burdensome. In current practice, most plausible gains in net clinical value will come from earlier and more precise patient selection, structured risk stratification using the APOE genotype and baseline magnetic resonance imaging status, strict management of vascular risk factors, intensified monitoring during the early hazard period, more personalized treatment exposure, and amyloid antibodies engineered for lower vascular toxicity, for example, using brain shuttle technology. Further, alternative routes of administration have the potential to reduce burden on patients, caregivers, and providers likewise. Real-world registries will be essential to define long-term safety, effectiveness, and treatment patterns outside clinical trial populations. Therefore, future improvement of amyloid-targeting treatments is likely to come from widening the therapeutic margin by drug engineering as well as precision implementation in real-world settings.},
}

@article {pmid42724471,
year = {2026},
author = {Li, X and Xu, L and Song, Q and Chu, Q},
title = {Exosomes: emerging biomarkers and therapeutic potential in postoperative delirium and postoperative cognitive dysfunction.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1854680},
pmid = {42724471},
issn = {2296-634X},
abstract = {BACKGROUND: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are common and clinically significant perioperative neurocognitive disorders that disproportionately affect elderly surgical patients. Despite their substantial impact on postoperative recovery and long-term outcomes, the lack of validated biomarkers and effective targeted therapies remains a major challenge in perioperative medicine.

Owing to their intrinsic ability to cross the blood-brain barrier and stably encapsulate central nervous system-derived biomolecules, exosomes have emerged as promising candidates for non-invasive biomarker discovery in POD and POCD. Disease-associated alterations in exosomal cargo, encompassing proteins such as P-tau and Aβ1-42, nucleic acids including miR-584-5p and circRNA_089763, and lipid-associated constituents, provide valuable molecular signatures for early diagnosis, disease stratification, prognostic assessment, and dynamic monitoring of perioperative neurocognitive disorders. It should be noted, however,that the majority of current evidence is extrapolated from Alzheimer's disease and other neurodegenerative conditions rather than directly validated in POD and POCD cohorts, and dedicated prospective studies remain warranted.

Exosomes exert therapeutic effects through two complementary mechanisms: serving as vehicles for targeted drug delivery and acting as endogenous neuroprotective mediators. Their excellent biocompatibility,low immunogenicity, and inherent capacity to traverse the blood-brain barrier render them attractive platforms for attenuating neuroinflammation, promoting synaptic repair, enhancing neurogenesis, and restoring blood-brain barrier integrity.

Despite their considerable promise, several challenges continue to impede clinical translation, including limitations in large-scale production, the lack of standardized isolation and characterization protocols, biological heterogeneity, and regulatory barriers. Future research should focus on establishing POD/POCD-specific exosomal biomarker panels, developing GMP-compliant manufacturing systems, engineering precision-targeted exosomal therapeutics, and conducting rigorous multicenter clinical studies to validate their safety and efficacy.

CONCLUSION: Exosomes hold substantial promise for transforming the diagnosis and treatment of POD and POCD. With continued advances in engineering technologies, mechanistic understanding, and clinical validation, exosome-based diagnostic and therapeutic strategies are expected to become an integral component of precision perioperative medicine.},
}